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An Updated Perspective on the Dual-Track Model of Enterocyte Fat Metabolism

  • Joshua R. Cook
    Affiliations
    Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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  • Alison B. Kohan
    Affiliations
    Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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  • Rebecca A. Haeusler
    Correspondence
    For correspondence: Rebecca A. Haeusler
    Affiliations
    Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Department of Pathology and Cell Biology; Columbia University College of Physicians and Surgeons, New York, NY, USA
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Open AccessPublished:September 09, 2022DOI:https://doi.org/10.1016/j.jlr.2022.100278

      Abstract

      The small intestinal epithelium has classically been envisioned as a conduit for nutrient absorption, but appreciation is growing for a larger and more dynamic role for enterocytes in lipid metabolism. Considerable gaps remain in our knowledge of this physiology, but it appears that the enterocyte’s structural polarization dictates its behavior in fat partitioning, treating fat differently based on its absorption across the apical versus the basolateral membrane. In this review, we synthesize existing data and thought on this dual-track model of enterocyte fat metabolism through the lens of human integrative physiology. The apical track includes the canonical pathway of dietary lipid absorption across the apical brush-border membrane, leading to packaging and secretion of those lipids as chylomicrons. However, this track also reserves a portion of dietary lipid within cytoplasmic lipid droplets for later uses, including the “second-meal effect,” which remains poorly understood. At the same time, the enterocyte takes up circulating fats across the basolateral membrane by mechanisms that may include receptor-mediated import of triglyceride-rich lipoproteins or their remnants, local hydrolysis and internalization of free fatty acids, or enterocyte de novo lipogenesis using basolaterally absorbed substrates. The ultimate destinations of basolateral-track fat may include fatty acid oxidation, structural lipid synthesis, storage in cytoplasmic lipid droplets, or ultimate resecretion, although the regulation and purposes of this basolateral track remain mysterious. We propose that the enterocyte integrates lipid flux along both of these tracks in order to calibrate its overall program of lipid metabolism.

      Supplementary key words

      Abbreviations:

      aCLD (apical CLD), bCLD (basolateral-track CLD), CLD (cytoplasmic lipid droplet), DNL (de novo lipogenesis), eDNL (Enterocyte de novo lipogenesis), FA (fatty acid), FAO (fatty acid oxidation), FFA (free fatty acid), GLP-1 (glucagon-like peptide-1), SME (second-meal effect), TG (triglyceride), TRL (triglyceride-rich lipoprotein)

      Preface

      In recent decades it has become apparent that intestinal fat handling extends beyond the purely absorptive. For one, the intestine senses and responds to bioactive signaling lipids, derived from the diet or the commensal microbes, but even as it pertains to bulk lipid homeostasis, we can now consider multiple facets of the enterocyte’s relationship with fat and how this intercalates into metabolism writ large. We therefore intend not to present an exhaustive recapitulation of the literature on this topic. Rather, we will synthesize the themes that emerge and analyze their potential connections to human health and disease. We focus on human data while using work from model systems to bridge knowledge gaps, and in both cases, we emphasize studies that are physiologically integrative. For expert review of the mechanistic details of intestinal lipid uptake, deposition, and remobilization, we refer the reader to multiple recent publications (
      • Ko C.W.
      • Qu J.
      • Black D.D.
      • Tso P.
      Regulation of intestinal lipid metabolism: current concepts and relevance to disease.
      ,
      • Wit M.
      • Trujillo-Viera J.
      • Strohmeyer A.
      • Klingenspor M.
      • Hankir M.
      • Sumara G.
      When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease.
      ,
      • Xiao C.
      • Stahel P.
      • Nahmias A.
      • Lewis G.F.
      Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization.
      ,
      • Stone S.J.
      Mechanisms of intestinal triacylglycerol synthesis.
      ,
      • Zhang B.
      • Kuipers F.
      • de Boer J.F.
      • Kuivenhoven J.A.
      Modulation of bile acid metabolism to improve plasma lipid and lipoprotein profiles.
      ,
      • Hoffman S.
      • Alvares D.
      • Adeli K.
      Intestinal lipogenesis: how carbs turn on triglyceride production in the gut.
      ,
      • Xiao C.
      • Stahel P.
      • Lewis G.F.
      Regulation of chylomicron secretion: focus on post-assembly mechanisms.
      ).

      Intestinal Reverse Lipid transport and the Dual-Track Hypothesis

      The canonical anterograde lipid-absorptive pathways within enterocytes have been extensively studied given their obvious physiologic importance. However, as early as the 1950s, evidence of reverse intestinal lipid trafficking, that is, transcellular efflux of cholesterol from the circulation into the intestinal lumen, began to emerge (
      • Cheng S.H.
      • Stanley M.M.
      Secretion of cholesterol by intestinal mucosa in patients with complete common bile duct obstruction.
      ,
      • Hellman L.
      • Rosenfeld R.S.
      • Eidinoff M.L.
      • Fukushima D.K.
      • Gallagher T.F.
      • Wang C.I.
      • et al.
      Isotopic studies of plasma cholesterol of endogenous and exogenous origins.
      ,
      • Stanley M.M.
      • Pineda E.P.
      • Cheng S.H.
      Serum cholesterol esters and intestinal cholesterol secretion and absorption in obstructive jaundice due to cancer.
      ,
      • Simmonds W.J.
      • Hofmann A.F.
      • Theodor E.
      Absorption of cholesterol from a micellar solution: intestinal perfusion studies in man.
      ,
      • Jakulj L.
      • van Dijk T.H.
      • de Boer J.F.
      • Kootte R.S.
      • Schonewille M.
      • Paalvast Y.
      • et al.
      Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion.
      ). The colocalization of cholesterol and triglycerides (TGs) within lipoproteins naturally raises the question of a parallel pathway for fats, and, in fact, there is general agreement that intestinal epithelial cells take up circulating fat across their basolateral membrane. Yet, unlike cholesterol, circulating fatty acids (FAs) are not known to undergo transintestinal excretion, calling into question the enterocyte’s purpose in taking them up.
      The very existence of substantial basolateral fat uptake and storage by the human enterocyte suggests some degree of participation in systemic fat metabolism beyond its canonical role in enteral nutrient absorption and secretion. A wealth of animal-based evidence substantiates this inference (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Li D.
      • Rodia C.N.
      • Johnson Z.K.
      • Bae M.
      • Muter A.
      • Heussinger A.E.
      • et al.
      Intestinal basolateral lipid substrate transport is linked to chylomicron secretion and is regulated by apoC-III.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Gangl A.
      • Ockner R.K.
      Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Role of the intestine in chylomicron remnant clearance.
      ,
      • Soued M.
      • Mansbach C.M.
      2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
      ) and suggests that lipid flux within the enterocyte operates on a dual-track system (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ). First, the canonical, or apical, pathway traffics in newly absorbed dietary fat, which may be directly secreted into lacteals as chylomicrons or deposited in dedicated cytoplasmic lipid droplets (CLDs) for later use. Second, the apical track is joined by an ill-defined basolateral counterpart comprising fat taken up from the blood and also stored in CLDs, but whose ultimate metabolic destiny remains largely unknown. Significantly, these two tracks appear to be segregated: lipids absorbed basolaterally seem to commingle little with those that the same cell has absorbed apically, suggesting distinct CLDs and cellular machinery subserving them (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ) (Figs. 1 and 2).
      Figure thumbnail gr1
      Fig. 1Dual-track model of enterocyte fat metabolism. The apical track is illustrated in yellow on the left side of the schematized enterocyte and the basolateral track on the right, in purple. Both tracks feature uptake of TG- or de novo lipogenesis (DNL)-derived fatty acids that are used to synthesize phospholipids (PLs), oxidized, or reesterified to TGs via the G3P (predominant in basolateral track) and GPAT (predominant in apical track) pathways. Reesterified TGs are stored in cytosolic lipid droplets in both tracks, and although bCLDs express a different complement of CLD-associated proteins than do aCLDs, these droplets or their contents may “cross-track.” The source of basolateral-track fatty acids—via uptake of VLDL or chylomicron remnants for intracellular hydrolysis versus extracellular TRL hydrolysis—remains unclear. Bile acids reabsorbed from the intestinal lumen also regulate enterocyte gene expression patterns before recirculating to the liver. Cholesterol taken up from the circulation is excreted via the basolateral track through the transintestinal cholesterol excretion (TICE) pathway.
      Figure thumbnail gr2
      Fig. 2Functional interaction of the dual tracks. Summary of known functions and interplay of the two enterocyte lipid tracks. The apical track, illustrated in yellow on the left side of the schematized enterocyte, demonstrates the absorption and utilization of dietary lipid, including re-esterification for storage in aCLD and/or chylomicron synthesis and secretion, phospholipid (PL) synthesis, and fatty acid (FA) oxidation. Additional apical track lipid is provided by de novo lipogenesis (DNL) from non-lipid precursors (e.g., carbohydrates) and perhaps “cross-tracking” of basal-track fats. These functions appear to be largely mirrored in the basolateral track, illustrated in purple at right, demonstrating a largely similar array of fates for circulating fats following basolateral uptake. However, there remain unknown aspects of basolateral track function remain.

      The Apical Track

      Although the apical track’s textbook role of importing dietary fat is obvious, closer examination reveals that the enterocyte is not merely a passive absorptive conduit. Rather, the enterocyte deliberately sequesters some of the fat that it brings on board within apical CLDs (aCLDs), implying a more dynamic role in the regulation of lipid metabolism.

      The second-meal effect

      Suspicion that the healthy intestine siloes at least a portion of absorbed lipid for later release originated in the repeated observation of a “second-meal effect” (SME), in which one lipid-rich meal apparently triggers an early surge in circulating apoB-48-containing intestinal triglyceride-rich lipoproteins (TRLs) during a second meal that occurs too quickly to be accounted for by the latter (
      • Cohn J.S.
      • McNamara J.R.
      • Krasinski S.D.
      • Russell R.M.
      • Schaefer E.J.
      Role of triglyceride-rich lipoproteins from the liver and intestine in the etiology of postprandial peaks in plasma triglyceride concentration.
      ,
      • Evans K.
      • Kuusela P.J.
      • Cruz M.L.
      • Wilhelmova I.
      • Fielding B.A.
      • Frayn K.N.
      Rapid chylomicron appearance following sequential meals: effects of second meal composition.
      ,
      • Fielding B.A.
      • Callow J.
      • Owen R.M.
      • Samra J.S.
      • Matthews D.R.
      • Frayn K.N.
      Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals.
      ,
      • Williams C.M.
      • Moore F.
      • Morgan L.
      • Wright J.
      Effects of n-3 fatty acids on postprandial triacylglycerol and hormone concentrations in normal subjects.
      ,
      • Jackson K.G.
      • Robertson M.D.
      • Fielding B.A.
      • Frayn K.N.
      • Williams C.M.
      Second meal effect: modified sham feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal.
      ,
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ,
      • Silva K.D.
      • Wright J.W.
      • Williams C.M.
      • Lovegrove J.A.
      Meal ingestion provokes entry of lipoproteins containing fat from the previous meal: possible metabolic implications.
      ,
      • Heath R.B.
      • Karpe F.
      • Milne R.W.
      • Burdge G.C.
      • Wootton S.A.
      • Frayn K.N.
      Dietary fatty acids make a rapid and substantial contribution to VLDL-triacylglycerol in the fed state.
      ). More compelling still, circulating chylomicron-TG levels still swiftly rise when the second meal is comprised solely of carbohydrates (i.e., fat free) (
      • Fielding B.A.
      • Callow J.
      • Owen R.M.
      • Samra J.S.
      • Matthews D.R.
      • Frayn K.N.
      Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals.
      ,
      • Robertson M.D.
      • Parkes M.
      • Warren B.F.
      • Ferguson D.J.
      • Jackson K.G.
      • Jewell D.P.
      • et al.
      Mobilisation of enterocyte fat stores by oral glucose in humans.
      ,
      • Hodson L.
      • McQuaid S.E.
      • Karpe F.
      • Frayn K.N.
      • Fielding B.A.
      Differences in partitioning of meal fatty acids into blood lipid fractions: a comparison of linoleate, oleate, and palmitate.
      ). Stable-isotope tracer studies have demonstrated that the chylomicron-TG appearing after later-meal ingestion may be derived from lipid intake more than 18 h prior (
      • Chavez-Jauregui R.N.
      • Mattes R.D.
      • Parks E.J.
      Dynamics of fat absorption and effect of sham feeding on postprandial lipema.
      ) and mirror the FA composition of the first meal (
      • Evans K.
      • Kuusela P.J.
      • Cruz M.L.
      • Wilhelmova I.
      • Fielding B.A.
      • Frayn K.N.
      Rapid chylomicron appearance following sequential meals: effects of second meal composition.
      ,
      • Fielding B.A.
      • Callow J.
      • Owen R.M.
      • Samra J.S.
      • Matthews D.R.
      • Frayn K.N.
      Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals.
      ,
      • Jackson K.G.
      • Robertson M.D.
      • Fielding B.A.
      • Frayn K.N.
      • Williams C.M.
      Second meal effect: modified sham feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal.
      ). The discovery of duodenal (
      • Xiao C.
      • Stahel P.
      • Carreiro A.L.
      • Hung Y.H.
      • Dash S.
      • Bookman I.
      • et al.
      Oral Glucose Mobilizes Triglyceride Stores From the Human Intestine.
      ) and jejunal (
      • Robertson M.D.
      • Parkes M.
      • Warren B.F.
      • Ferguson D.J.
      • Jackson K.G.
      • Jewell D.P.
      • et al.
      Mobilisation of enterocyte fat stores by oral glucose in humans.
      ) enterocytic CLDs in human intestinal biopsy specimens corroborated the intestinal storage of dietary fat inferred from the second-meal effect. Two SME studies in humans documented fewer (
      • Xiao C.
      • Stahel P.
      • Carreiro A.L.
      • Hung Y.H.
      • Dash S.
      • Bookman I.
      • et al.
      Oral Glucose Mobilizes Triglyceride Stores From the Human Intestine.
      ) and smaller (
      • Robertson M.D.
      • Parkes M.
      • Warren B.F.
      • Ferguson D.J.
      • Jackson K.G.
      • Jewell D.P.
      • et al.
      Mobilisation of enterocyte fat stores by oral glucose in humans.
      ,
      • Xiao C.
      • Stahel P.
      • Carreiro A.L.
      • Hung Y.H.
      • Dash S.
      • Bookman I.
      • et al.
      Oral Glucose Mobilizes Triglyceride Stores From the Human Intestine.
      ) CLDs per cell on biopsy if subjects ingested a carbohydrate load versus water at 5–6 h after a high-fat first meal, suggesting selective CLD depletion to serve the SME. However, biopsies were not taken after an overnight fast or in the immediate first-meal postprandial period to allow for direct comparisons of individuals’ CLD morphology over time (
      • Robertson M.D.
      • Parkes M.
      • Warren B.F.
      • Ferguson D.J.
      • Jackson K.G.
      • Jewell D.P.
      • et al.
      Mobilisation of enterocyte fat stores by oral glucose in humans.
      ,
      • Xiao C.
      • Stahel P.
      • Carreiro A.L.
      • Hung Y.H.
      • Dash S.
      • Bookman I.
      • et al.
      Oral Glucose Mobilizes Triglyceride Stores From the Human Intestine.
      ).
      Alternative lipid sources may also contribute to the observed SME. For instance, enterocytes recover FAs derived from biliary phospholipid excretion for esterification to TGs (
      • Zierenberg O.
      • Grundy S.M.
      Intestinal absorption of polyenephosphatidylcholine in man.
      ) and biliary phospholipids themselves are recycled as chylomicron coating (
      • Werner A.
      • Havinga R.
      • Perton F.
      • Kuipers F.
      • Verkade H.J.
      Lymphatic chylomicron size is inversely related to biliary phospholipid secretion in mice.
      ,
      • Tso P.
      • Kendrick H.
      • Balint J.A.
      • Simmonds W.J.
      Role of biliary phosphatidylcholine in the absorption and transport of dietary triolein in the rat.
      ). Thus, as duodenal entry even of pure carbohydrate triggers some bile excretion (
      • Fiamoncini J.
      • Yiorkas A.M.
      • Gedrich K.
      • Rundle M.
      • Alsters S.I.
      • Roeselers G.
      • et al.
      Determinants of postprandial plasma bile acid kinetics in human volunteers.
      ,
      • Liddle R.A.
      • Goldfine I.D.
      • Rosen M.S.
      • Taplitz R.A.
      • Williams J.A.
      Cholecystokinin bioactivity in human plasma. molecular forms, responses to feeding, and relationship to gallbladder contraction.
      ), the SME might represent the reappearance of biliary phospholipid-derived FAs in TGs. It is worth noting that only about 50% of bile is stored in the gallbladder during fasting and released with a meal; the other half drains into the duodenum, even during fasting (
      • Hofmann A.F.
      The continuing importance of bile acids in liver and intestinal disease.
      ). Indeed, during fasting, biliary lipids are the primary sources of lipids in the mesenteric lymph (
      • Shrivastava B.K.
      • Redgrave T.G.
      • Simmonds W.J.
      The source of endogenous lipid in the thoracic duct lymph of fasting rats.
      ). Because glycerolipid hydrolysis reesterification likely proceeds too slowly for phospholipids from postprandial gallbladder emptying to account for the SME (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ), SME TG may draw upon biliary lipids absorbed during fasting or a prior meal.
      Although the existence of the SME is clear in a phenomenological sense, its biological basis and purpose remain hazy. This has been difficult to sort out experimentally as the SME has been difficult to model in mice (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ); we present a few hypotheses worth considering. First, early mobilization of reserved dietary fat may “prime the pump” to efficiently ramp up the postprandial chylomicron assembly line (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ,
      • Martins I.J.
      • Sainsbury A.J.
      • Mamo J.C.
      • Redgrave T.G.
      Lipid and apolipoprotein B48 transport in mesenteric lymph and the effect of hyperphagia on the clearance of chylomicron-like emulsions in insulin-deficient rats.
      ). This may be particularly important when FA species enzymatically preferred—or perhaps even required—for TG esterification are limiting (
      • Karupaiah T.
      • Sundram K.
      Effects of stereospecific positioning of fatty acids in triacylglycerol structures in native and randomized fats: a review of their nutritional implications.
      ). Another possible explanation for the SME is that constitutive low-level chylomicron production from aCLDs (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ,
      • Björnson E.
      • Packard C.J.
      • Adiels M.
      • Andersson L.
      • Matikainen N.
      • Söderlund S.
      • et al.
      Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics.
      ) protects other tissues from large TG excursions due to lipoprotein lipase saturation (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ), although the SME would not be optimally timed for this purpose. On the other hand, intestinal lipid stockpiling may act as a defense against starvation. If so, then the renewed availability of dietary nutrients would temporarily relieve the intestine of this responsibility. In this vein, the SME may prove an exercise in self-defense if it represents a hurried divestiture of banked TGs in anticipation of a glut of new dietary fat. Because the enterocyte can foresee neither the quantity nor the composition of fat that it will ultimately encounter over the course of the meal, it would be prudent to ensure optimal readiness of its finite machinery to process the incoming lipid load. Once it has averted the threat of acute FA overload, the intestine can then restock its cache with fresh TGs, perhaps to ration as needed during fasting. Note that each of these hypotheses involves a preparatory action on the part of the enterocyte; this would square with SME triggering by “cephalic-phase” nutrient sensing (i.e., based on taste and smell), ostensibly as an early warning system of an impending food bolus (
      • Chavez-Jauregui R.N.
      • Mattes R.D.
      • Parks E.J.
      Dynamics of fat absorption and effect of sham feeding on postprandial lipema.
      ,
      • Mattes R.D.
      Brief oral stimulation, but especially oral fat exposure, elevates serum triglycerides in humans.
      ).

      The apical track beyond the second-meal effect

      Whatever its purpose, the SME casts aCLDs as more than just a brief stopover for TGs waiting their turn to be packaged in chylomicrons. As alluded to above, aCLDs allow enterocytic participation in quantitative and qualitative FA balance, a theme likely common to both tracks. Because of inherent enzymatic substrate preferences, the enterocyte scrambles the original FA composition of dietary TGs in their reassembly for chylomicron packaging (
      • Karupaiah T.
      • Sundram K.
      Effects of stereospecific positioning of fatty acids in triacylglycerol structures in native and randomized fats: a review of their nutritional implications.
      ), hence the distinct FA composition of dietary versus circulating TGs after a meal (
      • Burdge G.C.
      • Powell J.
      • Calder P.C.
      Lack of effect of meal fatty acid composition on postprandial lipid, glucose and insulin responses in men and women aged 50-65 years consuming their habitual diets.
      ,
      • Kayden H.J.
      • Karmen A.
      • Dumont A.
      Alterations in the Fatty acid composition of human lymph and serum lipoproteins by single feedings.
      ,
      • Karmen A.
      • Whyte M.
      • Goodman D.S.
      Fatty acid esterification and chylomicron formation during fat absorption. 1. Triglycerides and cholesterol esters.
      ). The enterocyte may therefore be able to call upon aCLDs as a clearinghouse to mix and match FAs for esterification as circumstances dictate (
      • Karmen A.
      • Whyte M.
      • Goodman D.S.
      Fatty acid esterification and chylomicron formation during fat absorption. 1. Triglycerides and cholesterol esters.
      ,
      • Zhu J.
      • Lee B.
      • Buhman K.K.
      • Cheng J.X.
      A dynamic, cytoplasmic triacylglycerol pool in enterocytes revealed by ex vivo and in vivo coherent anti-Stokes Raman scattering imaging.
      ,
      • Seyer A.
      • Cantiello M.
      • Bertrand-Michel J.
      • Roques V.
      • Nauze M.
      • Bézirard V.
      • et al.
      Lipidomic and spatio-temporal imaging of fat by mass spectrometry in mice duodenum during lipid digestion.
      ).
      We can look as well to the external signals that influence nutrient flux along the apical track for insights into its other roles. Bile acids promote secretion of incretin hormones and other neuropeptides by enteroendocrine cells (
      • Kuhre R.E.
      • Wewer Albrechtsen N.J.
      • Larsen O.
      • Jepsen S.L.
      • Balk-Møller E.
      • Andersen D.B.
      • et al.
      Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.
      ,
      • Christiansen C.B.
      • Trammell S.A.J.
      • Wewer Albrechtsen N.J.
      • Schoonjans K.
      • Albrechtsen R.
      • Gillum M.P.
      • et al.
      Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents.
      ,
      • Tough I.R.
      • Schwartz T.W.
      • Cox H.M.
      Synthetic G protein-coupled bile acid receptor agonists and bile acids act via basolateral receptors in ileal and colonic mucosa.
      ,
      • Hansen M.
      • Scheltema M.J.
      • Sonne D.P.
      • Hansen J.S.
      • Sperling M.
      • Rehfeld J.F.
      • et al.
      Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion.
      ,
      • McGlone E.R.
      • Malallah K.
      • Cuenco J.
      • Wewer Albrechtsen N.J.
      • Holst J.J.
      • Vincent R.P.
      • et al.
      Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.
      ) and fibroblast growth factor-19 (FGF-19) secretion by enterocytes (
      • Meyer-Gerspach A.C.
      • Steinert R.E.
      • Keller S.
      • Malarski A.
      • Schulte F.H.
      • Beglinger C.
      Effects of chenodeoxycholic acid on the secretion of gut peptides and fibroblast growth factors in healthy humans.
      ). Typifying the former, glucagon-like peptide-1 (GLP-1) receptor agonist administration both to healthy volunteers (
      • Xiao C.
      • Bandsma R.H.
      • Dash S.
      • Szeto L.
      • Lewis G.F.
      Exenatide, a glucagon-like peptide-1 receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans.
      ) and to patients with type 2 diabetes (
      • Schwartz E.A.
      • Koska J.
      • Mullin M.P.
      • Syoufi I.
      • Schwenke D.C.
      • Reaven P.D.
      Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus.
      ) acutely diminishes postprandial secretion of apoB-48-containing TRL, while GLP-2 administration does just the opposite (
      • Dash S.
      • Xiao C.
      • Morgantini C.
      • Connelly P.W.
      • Patterson B.W.
      • Lewis G.F.
      Glucagon-like peptide-2 regulates release of chylomicrons from the intestine.
      ). Attenuation of TG secretion by GLP-1 may, for example, help to coordinate the systemic after-meal switch to preferential utilization of glucose over fat (
      • Randle P.J.
      • Garland P.B.
      • Hales C.N.
      • Newsholme E.A.
      The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
      ), which in turn could entail temporary sequestration of a portion of dietary TGs in aCLDs. As human enterocytes do not express GLP receptors (
      • Dash S.
      • Xiao C.
      • Morgantini C.
      • Connelly P.W.
      • Patterson B.W.
      • Lewis G.F.
      Glucagon-like peptide-2 regulates release of chylomicrons from the intestine.
      ,
      • Pyke C.
      • Heller R.S.
      • Kirk R.K.
      • Ørskov C.
      • Reedtz-Runge S.
      • Kaastrup P.
      • et al.
      GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody.
      ), these observations reflect indirect regulation via some intermediary—perhaps through signals from neighboring cells or secondary to incretin-stimulated insulin secretion.
      Alterations of gut hormones may represent only a portion of the lipid-regulatory activities of bile acids in the intestine. Treatment with chenodeoxycholic acid, an endogenous human bile acid species, lowers TGs in hyperlipidemic patients (
      • Bateson M.C.
      • Maclean D.
      • Evans J.R.
      • Bouchier I.A.
      Chenodeoxycholic acid therapy for hypertriglyceridaemia in men.
      ,
      • Carulli N.
      • Ponz de Leon M.
      • Podda M.
      • Zuin M.
      • Strata A.
      • Frigerio G.
      • et al.
      Chenodeoxycholic acid and ursodeoxycholic acid effects in endogenous hypertriglyceridemias. A controlled double-blind trial.
      ), while bile acid-binding resins acutely lower circulating bile acids and raise TGs (
      • Sjöberg B.G.
      • Straniero S.
      • Angelin B.
      • Rudling M.
      Cholestyramine treatment of healthy humans rapidly induces transient hypertriglyceridemia when treatment is initiated.
      ,
      • Brønden A.
      • Mikkelsen K.
      • Sonne D.P.
      • Hansen M.
      • Våben C.
      • Gabe M.N.
      • et al.
      Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer.
      ). The molecular mechanism of this well-known observation remains enigmatic (
      • Sjöberg B.G.
      • Straniero S.
      • Angelin B.
      • Rudling M.
      Cholestyramine treatment of healthy humans rapidly induces transient hypertriglyceridemia when treatment is initiated.
      ); it may arise from bile acid regulation of chylomicron secretion (
      • Weintraub M.S.
      • Eisenberg S.
      • Breslow J.L.
      Different patterns of postprandial lipoprotein metabolism in normal, type IIa, type III, and type IV hyperlipoproteinemic individuals. Effects of treatment with cholestyramine and gemfibrozil.
      ) and/or from direct or indirect (cf. FGF-15/19) bile acid stimulation of hepatic de novo lipogenesis (DNL) (
      • Herrema H.
      • Meissner M.
      • van Dijk T.H.
      • Brufau G.
      • Boverhof R.
      • Oosterveer M.H.
      • et al.
      Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptor alpha-controlled metabolic pathways in mice.
      • Kim Y.C.
      • Seok S.
      • Zhang Y.
      • Ma J.
      • Kong B.
      • Guo G.
      • et al.
      Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A.
      ).

      Laying the Groundwork for a Basolateral Track

      Origins of basolateral-track fats

      While dietary lipids are the source of apical track substrates, the source of lipids for the basolateral track is less clear. Before considering the purpose of a basolateral track, it would be useful first to establish that lipids would enter the basolateral track through an actively regulated, singular process in enterocytes. Such possibilities include (re)esterification of basolaterally absorbed free fatty acids (FFAs), basolateral TRL-TG reuptake, or intestinal DNL from circulating carbohydrate precursors. Each of the possibilities is supported by existing data, albeit with varying degrees of directness.

      (Re)esterification of basolaterally absorbed free FA and glycerol

      Basolateral uptake of circulating FAs by enterocytes has been well established in animal models (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Gangl A.
      • Ockner R.K.
      Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.
      ,
      • Renner F.
      • Schernthaner G.
      • Gangl A.
      Intestinal metabolism of plasma free fatty acids in streptozotocin diabetic rats.
      ,
      • Lewis G.F.
      • Naples M.
      • Uffelman K.
      • Leung N.
      • Szeto L.
      • Adeli K.
      Intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids in the fasting state: studies in insulin-resistant and insulin-sensitized Syrian golden hamsters.
      ). There is also human in vivo evidence of basolateral uptake as an ultimate source of TRL-TG: 14C-palmitate infused intravenously was recovered within minutes in jejunal biopsy homogenates (
      • Gangl A.
      • Renner F.
      In vivo metabolism of plasma free fatty acids by intestinal mucosa of man.
      ), and IV-infused deuterated glycerol reappeared within circulating chylomicron-TG (
      • Shojaee-Moradie F.
      • Ma Y.
      • Lou S.
      • Hovorka R.
      • Umpleby A.M.
      Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol.
      ). Additionally, positron emission tomography imaging demonstrated duodenal and jejunal avidity for 18FTHA, a nonoxidizable palmitate analogue, in both lean and, to a greater extent, obese humans (
      • Koffert J.
      • Ståhle M.
      • Karlsson H.
      • Iozzo P.
      • Salminen P.
      • Roivainen A.
      • et al.
      Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow.
      ). These important studies, however, lacked the spatial resolution necessary to localize their findings specifically to enterocytes versus the extraenterocellular lamina propria (
      • Soriguer F.
      • García-Serrano S.
      • Garrido-Sánchez L.
      • Gutierrez-Repiso C.
      • Rojo-Martínez G.
      • Garcia-Escobar E.
      • et al.
      Jejunal wall triglyceride concentration of morbidly obese persons is lower in those with type 2 diabetes mellitus.
      ).
      The metabolic fate of FFAs within enterocytes may differ by site of uptake, in keeping with the dual-track model. In both animals (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Gangl A.
      • Ockner R.K.
      Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.
      ) and humans (
      • Gangl A.
      • Renner F.
      In vivo metabolism of plasma free fatty acids by intestinal mucosa of man.
      ), apical FFAs are mainly esterified to TGs, while the fate of basolateral FFAs has traditionally has been seen primarily as oxidation or incorporation into phospholipids (
      • Ko C.W.
      • Qu J.
      • Black D.D.
      • Tso P.
      Regulation of intestinal lipid metabolism: current concepts and relevance to disease.
      ). It is not necessarily surprising, however, that basolaterally absorbed FFAs were found to be principally destined for oxidation or structural lipid synthesis, as studies were generally performed in the fasting state. As fasting may impel enterocytes, as other cells, to rely more heavily on β-oxidation of FAs as an energy source, the destiny of basolateral FFAs could coordinately differ under fed conditions (
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Soued M.
      • Mansbach C.M.
      2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
      ). Consistent with this possibility, intravenously infused tritiated oleate continued to be taken up by the intestinal mucosa during concomitant enteral administration of glyceryl trioleates in rats; intestinal mucosal specific activity was recovered almost entirely esterified within TGs (
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ). Only a small proportion of this basolaterally derived TGs was ultimately incorporated into chylomicrons, again consistent with the dual-track hypothesis (
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ). Although comparable human tissue-level data are not available, intravenous infusion of a lipid emulsion in fed healthy volunteers acutely ramped up apoB-48 production (i.e., chylomicron secretion) without affecting its catabolism (
      • Duez H.
      • Lamarche B.
      • Valéro R.
      • Pavlic M.
      • Proctor S.
      • Xiao C.
      • et al.
      Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans.
      ). Thus, to the extent that this rise in apoB-48 production reflects augmented availability of TGs derived from basolaterally delivered FFAs, the rat data suggest that the enterocyte stows away an even larger share of that newly esterified TGs in basolateral-track CLDs (bCLDs) than it secretes (
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Duez H.
      • Lamarche B.
      • Valéro R.
      • Pavlic M.
      • Proctor S.
      • Xiao C.
      • et al.
      Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans.
      ). The track-differential routing of FFAs into TG synthesis may be reinforced by distinctive methods of reesterification (
      • Johnston J.M.
      • Rao G.A.
      • Lowe P.A.
      The separation of the alpha-glycerophosphate and monoglyceride pathways in the intestinal biosynthesis of triglycerides.
      ): the apical track primarily utilizes the less common monoacylglycerol pathway (
      • Kayden H.J.
      • Senior J.R.
      • Mattson F.H.
      The monoglyceride pathway of fat absorption in man.
      ,
      • Nelson D.W.
      • Gao Y.
      • Yen M.I.
      • Yen C.L.
      Intestine-specific deletion of acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 protects mice from diet-induced obesity and glucose intolerance.
      ), while the basolateral track may favor the more widely used glycerol-3-phosphate pathway (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Johnston J.M.
      • Rao G.A.
      • Lowe P.A.
      The separation of the alpha-glycerophosphate and monoglyceride pathways in the intestinal biosynthesis of triglycerides.
      ,
      • Kennedy E.P.
      • Weiss S.B.
      The function of cytidine coenzymes in the biosynthesis of phospholipides.
      ).

      Basolaterally absorbed lipoprotein-TG

      The enterocyte lipid pool may draw upon FA/TG taken up basolaterally from lipoproteins, perhaps in the form of recently secreted chylomicrons or recirculated chylomicron remnants (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Role of the intestine in chylomicron remnant clearance.
      ,
      • Soued M.
      • Mansbach C.M.
      2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
      ). As with other cells in the body, these lipoprotein-derived fats may undergo basolateral absorption as holoparticles entering the endolysosomal system or as FFAs locally derived from extracellular hydrolysis (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Soued M.
      • Mansbach C.M.
      2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
      ). Concordantly, both basolateral uptake of TRL/remnants and the constituent TG’s subsequent resecretion as chylomicrons have been demonstrated in rodent enterocytes (
      • Li D.
      • Rodia C.N.
      • Johnson Z.K.
      • Bae M.
      • Muter A.
      • Heussinger A.E.
      • et al.
      Intestinal basolateral lipid substrate transport is linked to chylomicron secretion and is regulated by apoC-III.
      ,
      • Soued M.
      • Mansbach C.M.
      2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
      ). Although these events have not yet been reported in humans, human enterocytes do express the LDL receptor on their basolateral surface (
      • Fong L.G.
      • Bonney E.
      • Kosek J.C.
      • Cooper A.D.
      Immunohistochemical localization of low density lipoprotein receptors in adrenal gland, liver, and intestine.
      ,
      • Sviridov D.
      • Hoeg J.M.
      • Eggerman T.
      • Demosky S.J.
      • Safonova I.G.
      • Brewer H.B.
      Low-density lipoprotein receptor and apolipoprotein A-I and B expression in human enterocytes.
      ), suggesting the capacity for uptake of apoB100/E-containing TRL. That HDL does not represent a major source of cholesterol for transintestinal cholesterol excretion in mice further implicates basolateral uptake of non-HDL particles by enterocytes as a potential source of TGs (
      • Groen A.K.
      • Bloks V.W.
      • Bandsma R.H.
      • Ottenhoff R.
      • Chimini G.
      • Kuipers F.
      Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.
      ). Yet, the failure of PCSK9 inhibitor treatment to meaningfully affect postprandial chylomicron-TG levels or apoB-48 secretion in humans argues against a central role for enterocyte LDLR in this process (
      • Reyes-Soffer G.
      • Pavlyha M.
      • Ngai C.
      • Thomas T.
      • Holleran S.
      • Ramakrishnan R.
      • et al.
      Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans.
      ,
      • Chan D.C.
      • Wong A.T.
      • Pang J.
      • Barrett P.H.
      • Watts G.F.
      Inter-relationships between proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III and plasma apolipoprotein B-48 transport in obese subjects: a stable isotope study in the postprandial state.
      ,
      • Taskinen M.R.
      • Björnson E.
      • Kahri J.
      • Söderlund S.
      • Matikainen N.
      • Porthan K.
      • et al.
      Effects of evolocumab on the postprandial kinetics of apo (Apolipoprotein) B100- and B48-containing lipoproteins in subjects with type 2 diabetes.
      ).

      Enterocyte de novo lipogenesis

      Enterocytes can also synthesize TGs from precursor substrates, and we surmise this includes those precursors taken up basolaterally from the circulation. Pure carbohydrate consumption increases circulating apoB-48 and chylomicron-TG levels in human volunteers, suggestive of human enterocyte DNL (
      • Egli L.
      • Lecoultre V.
      • Theytaz F.
      • Campos V.
      • Hodson L.
      • Schneiter P.
      • et al.
      Exercise prevents fructose-induced hypertriglyceridemia in healthy young subjects.
      ,
      • Xiao C.
      • Dash S.
      • Morgantini C.
      • Lewis G.F.
      Novel role of enteral monosaccharides in intestinal lipoprotein production in healthy humans.
      ,
      • Harbis A.
      • Perdreau S.
      • Vincent-Baudry S.
      • Charbonnier M.
      • Bernard M.C.
      • Raccah D.
      • et al.
      Glycemic and insulinemic meal responses modulate postprandial hepatic and intestinal lipoprotein accumulation in obese, insulin-resistant subjects.
      ). Enterocyte de novo lipogenesis (eDNL) with coordinately increased chylomicron production has been conclusively demonstrated in rodent enterocytes (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Haidari M.
      • Leung N.
      • Mahbub F.
      • Uffelman K.D.
      • Kohen-Avramoglu R.
      • Lewis G.F.
      • et al.
      Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction.
      ,
      • Al-Jawadi A.
      • Patel C.R.
      • Shiarella R.J.
      • Romelus E.
      • Auvinen M.
      • Guardia J.
      • et al.
      Cell-type-specific, ketohexokinase-dependent induction by fructose of lipogenic gene expression in mouse small intestine.
      ), while human enterocytes at a minimum do show mRNA expression of the full suite of required enzymes, including acetyl coA carboxylase and FA synthase (
      • Gutierrez-Repiso C.
      • Rodriguez-Pacheco F.
      • Garcia-Arnes J.
      • Valdes S.
      • Gonzalo M.
      • Soriguer F.
      • et al.
      The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance.
      ). Active DNL has not yet been specifically demonstrated in human enterocytes, but human duodenal explants do exhibit wholesale DNL (
      • Veilleux A.
      • Grenier E.
      • Marceau P.
      • Carpentier A.C.
      • Richard D.
      • Levy E.
      Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
      ), and in vivo stable-isotope tracer studies have documented incorporation of moieties derived from enteral fructose (
      • Theytaz F.
      • de Giorgi S.
      • Hodson L.
      • Stefanoni N.
      • Rey V.
      • Schneiter P.
      • et al.
      Metabolic fate of fructose ingested with and without glucose in a mixed meal.
      ,
      • Surowska A.
      • De Giorgi S.
      • Theytaz F.
      • Campos V.
      • Hodson L.
      • Stefanoni N.
      • et al.
      Effects of roux-en-Y gastric bypass surgery on postprandial fructose metabolism.
      ) and from intravenous glycerol (
      • Steenson S.
      • Shojaee-Moradie F.
      • B. Whyte M.
      • G. Jackson K.
      • Lovegrove J.A.
      • A. Fielding B.
      • et al.
      The effect of fructose feeding on intestinal triacylglycerol production and de novo fatty acid synthesis in humans.
      ) in chylomicron-palmitate. The additional time required for eDNL from carbohydrate delays the secretion of resultant chylomicron-FA/TG and apoB-48, represented as a shoulder or second peak on the curve, after the absorption of the dietary lipid component of the original meal. Interestingly, the second peaks of apoB-48 and chylomicron-lipids coincide with, or even follow, the postprandial rise in hepatic apoB-100 and VLDL secretion (
      • Xiao C.
      • Dash S.
      • Morgantini C.
      • Lewis G.F.
      Novel role of enteral monosaccharides in intestinal lipoprotein production in healthy humans.
      ,
      • Harbis A.
      • Perdreau S.
      • Vincent-Baudry S.
      • Charbonnier M.
      • Bernard M.C.
      • Raccah D.
      • et al.
      Glycemic and insulinemic meal responses modulate postprandial hepatic and intestinal lipoprotein accumulation in obese, insulin-resistant subjects.
      ,
      • Theytaz F.
      • de Giorgi S.
      • Hodson L.
      • Stefanoni N.
      • Rey V.
      • Schneiter P.
      • et al.
      Metabolic fate of fructose ingested with and without glucose in a mixed meal.
      ,
      • Surowska A.
      • De Giorgi S.
      • Theytaz F.
      • Campos V.
      • Hodson L.
      • Stefanoni N.
      • et al.
      Effects of roux-en-Y gastric bypass surgery on postprandial fructose metabolism.
      ), and rates of hepatic and intestinal DNL appear to be very tightly correlated (
      • Steenson S.
      • Shojaee-Moradie F.
      • B. Whyte M.
      • G. Jackson K.
      • Lovegrove J.A.
      • A. Fielding B.
      • et al.
      The effect of fructose feeding on intestinal triacylglycerol production and de novo fatty acid synthesis in humans.
      ). These observations leave open the possibility, mentioned above, that at least some of the second rise in chylomicron secretion attributed to eDNL may actually reflect basolateral uptake and reprocessing of recirculated, hepatically derived lipids.

      Distinguishing basolateral CLDs

      If the basolateral track does contribute to the enterocyte lipid pool by any or all of the above mechanisms, dedicated bCLD could, speculatively, enable spatiotemporal control over enterocyte lipid-metabolic processes. This, however, would require recognition and differential regulation of two coexisting CLD populations: aCLD versus bCLD. Mouse duodenal enterocytes have been found to contain CLDs whose lipid makeup clearly differs from those in other cell types (
      • Seyer A.
      • Cantiello M.
      • Bertrand-Michel J.
      • Roques V.
      • Nauze M.
      • Bézirard V.
      • et al.
      Lipidomic and spatio-temporal imaging of fat by mass spectrometry in mice duodenum during lipid digestion.
      ). Enterocyte CLDs also feature an adipocyte-like complement of lipid droplet-associated proteins (
      • Bouchoux J.
      • Beilstein F.
      • Pauquai T.
      • Guerrera I.C.
      • Chateau D.
      • Ly N.
      • et al.
      The proteome of cytosolic lipid droplets isolated from differentiated Caco-2/TC7 enterocytes reveals cell-specific characteristics.
      • Beilstein F.
      • Bouchoux J.
      • Rousset M.
      • Demignot S.
      Proteomic analysis of lipid droplets from Caco-2/TC7 enterocytes identifies novel modulators of lipid secretion.
      ) that may further distinguish bCLD from apical (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Seyer A.
      • Cantiello M.
      • Bertrand-Michel J.
      • Roques V.
      • Nauze M.
      • Bézirard V.
      • et al.
      Lipidomic and spatio-temporal imaging of fat by mass spectrometry in mice duodenum during lipid digestion.
      ). Mouse enterocyte-specific knockout of two major CLD-associated proteins, adipose TG lipase and comparative gene identification-58 (CGI-58), results in massive enteral steatosis despite untrammeled dietary fat absorption and chylomicron secretion (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ). The selective enterocytic accumulation of intravenously administered FAs, on the other hand, implies that the missing proteins specifically regulate bCLD (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Korbelius M.
      • Vujić N.
      • Kuentzel K.B.
      • Obrowsky S.
      • Rainer S.
      • Haemmerle G.
      • et al.
      Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis.
      ), consistent with a unique bCLD identity.

      Exploring the Significance of the Basolateral Track

      Housekeeping functions

      If we accept the above observations as evidence that basolateral track represents a discrete, organized process, we next consider its physiologic relevance (Fig. 2). The prevailing thinking on the matter, based largely on animal studies, tends to treat the basolateral track as subserving “housekeeping” functions within the enterocyte during fasting: providing a wellspring of energetic substrates to tide the cell over until the next meal and preferred FA species for structural-lipid synthesis (
      • Ko C.W.
      • Qu J.
      • Black D.D.
      • Tso P.
      Regulation of intestinal lipid metabolism: current concepts and relevance to disease.
      ,
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Gangl A.
      • Ockner R.K.
      Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Role of the intestine in chylomicron remnant clearance.
      ,
      • Gangl A.
      • Renner F.
      In vivo metabolism of plasma free fatty acids by intestinal mucosa of man.
      ). Although up to 30% of basolateral-track FAs may be oxidized during fasting (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ), FAs do not appear to be major drivers of enterocyte ATP generation in either the fed (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Windmueller H.G.
      • Spaeth A.E.
      Identification of ketone bodies and glutamine as the major respiratory fuels in vivo for postabsorptive rat small intestine.
      ,
      • Windmueller H.G.
      • Spaeth A.E.
      Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate, and aspartate.
      ) or fasted states (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Newsholme P.
      • Procopio J.
      • Lima M.M.
      • Pithon-Curi T.C.
      • Curi R.
      Glutamine and glutamate--their central role in cell metabolism and function.
      ) on a background of normal dietary fat content. Moreover, to the extent that enterocytes do engage in fatty acid oxidation (FAO) during energy-intensive meal absorption, most such fuel is apically derived (
      • Gangl A.
      • Ockner R.K.
      Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.
      ).
      We therefore confront a conundrum: enterocytes evidently possess robust cellular machinery for uptake and oxidation of circulating FAs, yet they seem not to use it primarily for energy generation, as cells typically do (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ). We can envisage a few hypothetical explanations for a beefed up β-oxidative apparatus in enterocytes that encompasses a larger scale and/or a broader purpose than enterocytic energy independence during fasting (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ). For example, if the enterocyte were also a “professionally” lipolytic cell, it might disburse hydrolyzed FAs locally to support other epithelial or lamina propria cells during fasting. Occurrence of such a phenomenon in vivo (e.g., calculations based on portal-drained viscera) (
      • Yen J.T.
      • Nienaber J.A.
      • Hill D.A.
      • Pond W.G.
      Oxygen consumption by portal vein-drained organs and by whole animal in conscious growing swine.
      ) or in explanted specimens of whole intestine would not necessarily have been experimentally localizable and therefore prone to conflation with enterocyte-specific FAO. Beyond metabolism, intestinal FAO also affects epithelial proliferation and survival due to its collateral impact on the intracellular redox state (
      • Aguilar E.
      • Esteves P.
      • Sancerni T.
      • Lenoir V.
      • Aparicio T.
      • Bouillaud F.
      • et al.
      UCP2 deficiency increases colon tumorigenesis by promoting lipid synthesis and depleting NADPH for antioxidant defenses.
      ). This may be a particularly important regulatory consideration in the tumorigenic setting of constant cell turnover and exposure to environmental toxins.

      Fat sensing

      We conjecture that enterocytes harness FAO as a means of nutrient sensing (Fig. 3). Just as pancreatic β-cells co-opt glucose metabolism as a nutrient-sensing mechanism for autoregulation of insulin secretion, so may enterocytes reappropriate FA metabolism as a barometer of systemic energy balance to which they can couple their own metaboregulatory activities (
      • Langhans W.
      • Leitner C.
      • Arnold M.
      Dietary fat sensing via fatty acid oxidation in enterocytes: possible role in the control of eating.
      ). This could occur, for example, through repurposing of FAO, which would also help to account for the enterocyte’s apparent excess capacity for FAO discussed above (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Langhans W.
      • Leitner C.
      • Arnold M.
      Dietary fat sensing via fatty acid oxidation in enterocytes: possible role in the control of eating.
      ). As enterocytes can take up and oxidize fat from recirculated chylomicron remnants (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Li D.
      • Rodia C.N.
      • Johnson Z.K.
      • Bae M.
      • Muter A.
      • Heussinger A.E.
      • et al.
      Intestinal basolateral lipid substrate transport is linked to chylomicron secretion and is regulated by apoC-III.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Role of the intestine in chylomicron remnant clearance.
      ,
      • Soued M.
      • Mansbach C.M.
      2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
      ), the internal calculus of basolateral- versus apical-track FAO could constitute a fat-sensing circuit. Potentially consistent with this interpretation, augmenting enterocyte FAO in mice increases energy expenditure during high-fat diet feeding (
      • Korbelius M.
      • Vujić N.
      • Kuentzel K.B.
      • Obrowsky S.
      • Rainer S.
      • Haemmerle G.
      • et al.
      Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis.
      ).
      Figure thumbnail gr3
      Fig. 3Hypothetical energy-sensing circuit, a model for interaction of apical and basolateral tracks. Fats traffic along pathways indicated by black arrows, while small quantities may be diverted along the red arrows for oxidative (i.e., via FA oxidation) or non-oxidative energy sensing to compare fat inputs and outputs as a barometer of systemic energy needs. An “energy sensor” may then control flux of fats along storage versus oxidation pathways on either track according to its homeostatic needs.
      Whether through FAO or even nonoxidative means, the construction of such a fat-sensing circuit would allow the enterocyte to monitor the equilibrium between dietary (i.e., apical) fat supply and systemic demand, the latter inversely proportional to the basolaterally returning chylomicron-remnant TGs not already siphoned by other tissues. This could underpin, for example, the intestine’s observed role in feedback regulation of food intake (
      • Langhans W.
      • Leitner C.
      • Arnold M.
      Dietary fat sensing via fatty acid oxidation in enterocytes: possible role in the control of eating.
      ). Although this concept is attractive and comports with some animal physiologic data (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ,
      • Nelson D.W.
      • Gao Y.
      • Yen M.I.
      • Yen C.L.
      Intestine-specific deletion of acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 protects mice from diet-induced obesity and glucose intolerance.
      ,
      • Karimian Azari E.
      • Leitner C.
      • Jaggi T.
      • Langhans W.
      • Mansouri A.
      Possible role of intestinal fatty acid oxidation in the eating-inhibitory effect of the PPAR-α agonist Wy-14643 in High-fat diet fed rats.
      ,
      • Mori T.
      • Kondo H.
      • Hase T.
      • Tokimitsu I.
      • Murase T.
      Dietary fish oil upregulates intestinal lipid metabolism and reduces body weight gain in C57BL/6J mice.
      ,
      • Ramachandran D.
      • Clara R.
      • Fedele S.
      • Michel L.
      • Burkard J.
      • Kaufman S.
      • et al.
      Enhancing enterocyte fatty acid oxidation in mice affects glycemic control depending on dietary fat.
      ), particularly the independent regulation of apical versus basolateral FAO based on feeding status (
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ), it remains a hypothesis in need of further testing (
      • Koffert J.
      • Ståhle M.
      • Karlsson H.
      • Iozzo P.
      • Salminen P.
      • Roivainen A.
      • et al.
      Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow.
      ,
      • Langhans W.
      • Leitner C.
      • Arnold M.
      Dietary fat sensing via fatty acid oxidation in enterocytes: possible role in the control of eating.
      ).
      Enterocyte signaling of nutrient status by any means likely requires cooperation with enteroendocrine cells, whose role in satiety and facilitation of insulin-mediated nutrient disposal is well established. For example, enterocyte nutrient-status feedback may be mediated in part via cholecystokinin production by enteroendocrine cells (
      • Covasa M.
      • Ritter R.C.
      Attenuated satiation response to intestinal nutrients in rats that do not express CCK-A receptors.
      ,
      • Matzinger D.
      • Degen L.
      • Drewe J.
      • Meuli J.
      • Duebendorfer R.
      • Ruckstuhl N.
      • et al.
      The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans.
      ). Bile acids may also play a role, given their dual functions of fat emulsification and digestion-timed signaling in multiple intestinal cell types. Bile acids reabsorbed into the circulation by ileal enterocytes go on to activate their cell-surface receptor GPBAR1 (a.k.a. TGR5) on the basolateral membranes of enteroendocrine cells (including L-cells, also enriched in the ileum) and various neurohormonal cells of the lamina propria (
      • Kuhre R.E.
      • Wewer Albrechtsen N.J.
      • Larsen O.
      • Jepsen S.L.
      • Balk-Møller E.
      • Andersen D.B.
      • et al.
      Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.
      ,
      • Christiansen C.B.
      • Trammell S.A.J.
      • Wewer Albrechtsen N.J.
      • Schoonjans K.
      • Albrechtsen R.
      • Gillum M.P.
      • et al.
      Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents.
      ,
      • Tough I.R.
      • Schwartz T.W.
      • Cox H.M.
      Synthetic G protein-coupled bile acid receptor agonists and bile acids act via basolateral receptors in ileal and colonic mucosa.
      ). In this way, bile acids contribute to the human intestine’s regulated secretion of the key gut hormones GLP-1 and peptide YY (
      • Kuhre R.E.
      • Wewer Albrechtsen N.J.
      • Larsen O.
      • Jepsen S.L.
      • Balk-Møller E.
      • Andersen D.B.
      • et al.
      Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.
      ,
      • Christiansen C.B.
      • Trammell S.A.J.
      • Wewer Albrechtsen N.J.
      • Schoonjans K.
      • Albrechtsen R.
      • Gillum M.P.
      • et al.
      Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents.
      ,
      • Tough I.R.
      • Schwartz T.W.
      • Cox H.M.
      Synthetic G protein-coupled bile acid receptor agonists and bile acids act via basolateral receptors in ileal and colonic mucosa.
      ,
      • Adrian T.E.
      • Ballantyne G.H.
      • Longo W.E.
      • Bilchik A.J.
      • Graham S.
      • Basson M.D.
      • et al.
      Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon.
      ). Although not proven experimentally, this regulatory scheme implicates the enterocyte as well in its capacity as a dynamic gatekeeper mediating the enterohepatic circulation of bile acids (
      • Coppola C.P.
      • Gosche J.R.
      • Arrese M.
      • Ancowitz B.
      • Madsen J.
      • Vanderhoof J.
      • et al.
      Molecular analysis of the adaptive response of intestinal bile acid transport after ileal resection in the rat.
      ,
      • Dawson P.A.
      • Karpen S.J.
      Intestinal transport and metabolism of bile acids.
      ). However, the manner and extent to which these extraenterocytic processes play in enterocyte lipid metabolism remains unclear.

      FA balance

      The enterocyte has access to a range of FA species from the diet that can be further strategically enriched by basolateral uptake of circulating lipoproteins and DNL (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Haidari M.
      • Leung N.
      • Mahbub F.
      • Uffelman K.D.
      • Kohen-Avramoglu R.
      • Lewis G.F.
      • et al.
      Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction.
      ,
      • Al-Jawadi A.
      • Patel C.R.
      • Shiarella R.J.
      • Romelus E.
      • Auvinen M.
      • Guardia J.
      • et al.
      Cell-type-specific, ketohexokinase-dependent induction by fructose of lipogenic gene expression in mouse small intestine.
      ). This may be important intracellularly to manage the high phospholipid throughput required for enterocytes’ constant cellular turnover (
      • Hall P.A.
      • Coates P.J.
      • Ansari B.
      • Hopwood D.
      Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis.
      ). As FA composition governs phospholipids’ essential structural properties (
      • Wang B.
      • Rong X.
      • Duerr M.A.
      • Hermanson D.J.
      • Hedde P.N.
      • Wong J.S.
      • et al.
      Intestinal phospholipid remodeling is required for dietary-lipid uptake and survival on a high-fat diet.
      ), we predict that this fundamental task requires active balancing of the cell’s FA repertoire.
      Balancing the FA reserve may also be important to curate appropriately structured phospholipids that sustain lipoprotein secretion (
      • Werner A.
      • Havinga R.
      • Perton F.
      • Kuipers F.
      • Verkade H.J.
      Lymphatic chylomicron size is inversely related to biliary phospholipid secretion in mice.
      ,
      • Tso P.
      • Kendrick H.
      • Balint J.A.
      • Simmonds W.J.
      Role of biliary phosphatidylcholine in the absorption and transport of dietary triolein in the rat.
      ,
      • Wang B.
      • Rong X.
      • Duerr M.A.
      • Hermanson D.J.
      • Hedde P.N.
      • Wong J.S.
      • et al.
      Intestinal phospholipid remodeling is required for dietary-lipid uptake and survival on a high-fat diet.
      ), and we speculate that ultimately it may influence the composition of the circulating FA/TG pool. In order to engage meaningfully in such a process, the basolateral track would need to influence not only the uptake of fats at the basolateral surface but also their secretion or resecretion. This process could entail some crossover of fat from the basolateral to the apical track (
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Shojaee-Moradie F.
      • Ma Y.
      • Lou S.
      • Hovorka R.
      • Umpleby A.M.
      Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol.
      ,
      • Duez H.
      • Lamarche B.
      • Valéro R.
      • Pavlic M.
      • Proctor S.
      • Xiao C.
      • et al.
      Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans.
      ). In so doing, basolaterally derived lipids might serve a constitutive, low-grade pump-priming function to maintain the readiness of the chylomicron assembly line and/or may even give rise to the SME (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Li D.
      • Rodia C.N.
      • Johnson Z.K.
      • Bae M.
      • Muter A.
      • Heussinger A.E.
      • et al.
      Intestinal basolateral lipid substrate transport is linked to chylomicron secretion and is regulated by apoC-III.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ,
      • Björnson E.
      • Packard C.J.
      • Adiels M.
      • Andersson L.
      • Matikainen N.
      • Söderlund S.
      • et al.
      Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics.
      ). Cross-tracking of bCLD lipids also potentially buffers the cytoplasmic concentrations of specific FA species to optimize esterification of chylomicron-bound TGs according to enzymatic substrate preferences (
      • Karupaiah T.
      • Sundram K.
      Effects of stereospecific positioning of fatty acids in triacylglycerol structures in native and randomized fats: a review of their nutritional implications.
      ).
      (Re)secretion of basolaterally derived fat could also reflect a separate basolateral lipid-secretory pathway, perhaps based on VLDL (
      • Kindel T.
      • Lee D.M.
      • Tso P.
      The mechanism of the formation and secretion of chylomicrons.
      ). Although the chylomicron is the small intestine’s canonical TRL, enterocytes are also capable of secreting apoB48-containing VLDL (i.e., distinguished operationally based on sedimentation rate), particularly during fasting (
      • Björnson E.
      • Packard C.J.
      • Adiels M.
      • Andersson L.
      • Matikainen N.
      • Söderlund S.
      • et al.
      Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics.
      ,
      • Tso P.
      • Drake D.S.
      • Black D.D.
      • Sabesin S.M.
      Evidence for separate pathways of chylomicron and very low-density lipoprotein assembly and transport by rat small intestine.
      ,
      • Ockner R.K.
      • Hughes F.B.
      • Isselbacher K.J.
      Very low density lipoproteins in intestinal lymph: origin, composition, and role in lipid transport in the fasting state.
      ,
      • Björnson E.
      • Packard C.J.
      • Adiels M.
      • Andersson L.
      • Matikainen N.
      • Söderlund S.
      • et al.
      Apolipoprotein B48 metabolism in chylomicrons and very low-density lipoproteins and its role in triglyceride transport in normo- and hypertriglyceridemic human subjects.
      ). This enterocyte VLDL production may occur independently of chylomicron production, and the resulting lipoproteins can differ in lipid composition (
      • Tso P.
      • Drake D.S.
      • Black D.D.
      • Sabesin S.M.
      Evidence for separate pathways of chylomicron and very low-density lipoprotein assembly and transport by rat small intestine.
      ,
      • Ockner R.K.
      • Hughes F.B.
      • Isselbacher K.J.
      Very low density lipoproteins in intestinal lymph: origin, composition, and role in lipid transport in the fasting state.
      ,
      • Björnson E.
      • Packard C.J.
      • Adiels M.
      • Andersson L.
      • Matikainen N.
      • Söderlund S.
      • et al.
      Apolipoprotein B48 metabolism in chylomicrons and very low-density lipoproteins and its role in triglyceride transport in normo- and hypertriglyceridemic human subjects.
      ,
      • Tso P.
      • Balint J.A.
      • Rodgers J.B.
      Effect of hydrophobic surfactant (Pluronic L-81) on lymphatic lipid transport in the rat.
      ,
      • Tso P.
      • Balint J.A.
      • Bishop M.B.
      • Rodgers J.B.
      Acute inhibition of intestinal lipid transport by Pluronic L-81 in the rat.
      ,
      • Ockner R.K.
      • Hughes F.B.
      • Isselbacher K.J.
      Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption.
      ). As many lipoprotein-kinetic studies have reported effects on TRL without distinguishing between particles of differing size or density, they may inadvertently have conflated two separate processes (
      • Björnson E.
      • Packard C.J.
      • Adiels M.
      • Andersson L.
      • Matikainen N.
      • Söderlund S.
      • et al.
      Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics.
      ).

      Enterocyte Lipid Storage in Metabolic Disease

      The apparent spatial and functional separation of bCLDs from those containing newly absorbed dietary fat (aCLD) (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ) makes it unclear a priori if bCLDs represent metabolic friend or foe. In other words, should this distinct bCLD pool be accorded the generally detrimental reputation of extraadipocellular “ectopic” lipid accumulation? Patients with chylomicron retention disease develop relatively enterocyte-specific massive apical CLD overload due to impaired intracellular trafficking of nascent chylomicrons (
      • Levy E.
      • Poinsot P.
      • Spahis S.
      Chylomicron retention disease: genetics, biochemistry, and clinical spectrum.
      ,
      • Peretti N.
      • Sassolas A.
      • Roy C.C.
      • Deslandres C.
      • Charcosset M.
      • Castagnetti J.
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      ). However, they do not appear syndromically prone to diabetes and, interestingly, have normal serum TGs, ostensibly due to augmented hepatic DNL (
      • Levy E.
      • Poinsot P.
      • Spahis S.
      Chylomicron retention disease: genetics, biochemistry, and clinical spectrum.
      ,
      • Peretti N.
      • Sassolas A.
      • Roy C.C.
      • Deslandres C.
      • Charcosset M.
      • Castagnetti J.
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      ). On the other hand, there are no known human disorders specifically of enterocyte bCLD metabolism. In fact, correlative human data suggest a beneficial role for enterocyte CLDs; SME magnitude, presumably reflecting the extent of prior-meal fat storage in CLD, associates positively with insulin sensitivity (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ). Congruently, a mouse model of specific bCLD accumulation manifests lower plasma TG and protection from hepatic steatosis versus control, although any potential effects on glucose metabolism were not reported (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ). However, reduction of CLDs by intestine-specific transgenic augmentation of lipolysis in mice does not affect TG levels (
      • Korbelius M.
      • Vujić N.
      • Kuentzel K.B.
      • Obrowsky S.
      • Rainer S.
      • Haemmerle G.
      • et al.
      Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis.
      ).
      If the enterocyte represents a qualified “safe haven” for short-term lipid banking, we imagine it, like adipose tissue or liver (
      • Petersen M.C.
      • Shulman G.I.
      Mechanisms of Insulin Action and Insulin Resistance.
      ), will come to fail in the face of chronic fat excess and its attendant insulin-desensitizing repercussions (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ). Insulin resistance and diabetes do appear to be associated with dysregulated intestinal lipid handling (
      • Shojaee-Moradie F.
      • Ma Y.
      • Lou S.
      • Hovorka R.
      • Umpleby A.M.
      Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol.
      ,
      • Koffert J.
      • Ståhle M.
      • Karlsson H.
      • Iozzo P.
      • Salminen P.
      • Roivainen A.
      • et al.
      Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow.
      ,
      • Curtin A.
      • Deegan P.
      • Owens D.
      • Collins P.
      • Johnson A.
      • Tomkin G.H.
      Elevated triglyceride-rich lipoproteins in diabetes. A study of apolipoprotein B-48.
      ,
      • Ohnishi H.
      • Saitoh S.
      • Takagi S.
      • Ohata J.
      • Isobe T.
      • Kikuchi Y.
      • et al.
      Relationship between insulin-resistance and remnant-like particle cholesterol.
      ,
      • Schaefer E.J.
      • McNamara J.R.
      • Shah P.K.
      • Nakajima K.
      • Cupples L.A.
      • Ordovas J.M.
      • et al.
      Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study.
      ,
      • Taniguchi A.
      • Fukushima M.
      • Sakai M.
      • Miwa K.
      • Makita T.
      • Nagata I.
      • et al.
      Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.
      ,
      • Nogueira J.P.
      • Maraninchi M.
      • Béliard S.
      • Padilla N.
      • Duvillard L.
      • Mancini J.
      • et al.
      Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes.
      ,
      • Phillips C.
      • Murugasu G.
      • Owens D.
      • Collins P.
      • Johnson A.
      • Tomkin G.H.
      Improved metabolic control reduces the number of postprandial apolipoprotein B-48-containing particles in type 2 diabetes.
      ,
      • Higgins V.
      • Adeli K.
      Postprandial dyslipidemia in insulin resistant states in adolescent populations.
      ,
      • Duvillard L.
      • Pont F.
      • Florentin E.
      • Galland-Jos C.
      • Gambert P.
      • Vergès B.
      Metabolic abnormalities of apolipoprotein B-containing lipoproteins in non-insulin-dependent diabetes: a stable isotope kinetic study.
      ,
      • Larsen M.A.
      • Goll R.
      • Lekahl S.
      • Moen O.S.
      • Florholmen J.
      Delayed clearance of triglyceride-rich lipoproteins in young, healthy obese subjects.
      ,
      • Paola Gutiérrez Castro K.
      • Patricia González A.
      • Caccavello R.
      • Garay-Sevilla M.E.
      • Gugliucci A.
      Lean adolescents with insulin resistance display higher angiopoietin like protein 3, ApoC-III and chylomicron remnant dyslipidemia.
      ,
      • Chan D.C.
      • Watts G.F.
      • Ng T.W.
      • Yamashita S.
      • Barrett P.H.
      Effect of weight loss on markers of triglyceride-rich lipoprotein metabolism in the metabolic syndrome.
      ). Fat consumption produces exaggerated spikes in postprandial chylomicron-TG in patients with insulin resistance or type 2 diabetes versus healthy controls (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ,
      • Shojaee-Moradie F.
      • Ma Y.
      • Lou S.
      • Hovorka R.
      • Umpleby A.M.
      Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol.
      ,
      • Curtin A.
      • Deegan P.
      • Owens D.
      • Collins P.
      • Johnson A.
      • Tomkin G.H.
      Elevated triglyceride-rich lipoproteins in diabetes. A study of apolipoprotein B-48.
      ,
      • Larsen M.A.
      • Goll R.
      • Lekahl S.
      • Moen O.S.
      • Florholmen J.
      Delayed clearance of triglyceride-rich lipoproteins in young, healthy obese subjects.
      ,
      • Lewis G.F.
      • O'Meara N.M.
      • Soltys P.A.
      • Blackman J.D.
      • Iverius P.H.
      • Pugh W.L.
      • et al.
      Fasting hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid and lipoprotein abnormalities.
      ,
      • Syvanne M.
      • Hilden H.
      • Taskinen M.R.
      Abnormal metabolism of postprandial lipoproteins in patients with non-insulin-dependent diabetes mellitus is not related to coronary artery disease.
      ,
      • Wong A.T.
      • Chan D.C.
      • Pang J.
      • Watts G.F.
      • Barrett P.H.
      Plasma apolipoprotein B-48 transport in obese men: a new tracer kinetic study in the postprandial state.
      ), and improved diabetes control attenuates postprandial chylomicron excursions (
      • Phillips C.
      • Murugasu G.
      • Owens D.
      • Collins P.
      • Johnson A.
      • Tomkin G.H.
      Improved metabolic control reduces the number of postprandial apolipoprotein B-48-containing particles in type 2 diabetes.
      ,
      • Matikainen N.
      • Mänttäri S.
      • Schweizer A.
      • Ulvestad A.
      • Mills D.
      • Dunning B.E.
      • et al.
      Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes.
      ). Mechanistically, these findings appear to result both from increases in apoB-48 production and decreases in its clearance, as well as enhanced uptake and esterification of basolaterally (re)absorbed FFA, in the setting of insulin resistance and diabetes (
      • Shojaee-Moradie F.
      • Ma Y.
      • Lou S.
      • Hovorka R.
      • Umpleby A.M.
      Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol.
      ,
      • Koffert J.
      • Ståhle M.
      • Karlsson H.
      • Iozzo P.
      • Salminen P.
      • Roivainen A.
      • et al.
      Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow.
      ,
      • Duvillard L.
      • Pont F.
      • Florentin E.
      • Galland-Jos C.
      • Gambert P.
      • Vergès B.
      Metabolic abnormalities of apolipoprotein B-containing lipoproteins in non-insulin-dependent diabetes: a stable isotope kinetic study.
      ,
      • Paola Gutiérrez Castro K.
      • Patricia González A.
      • Caccavello R.
      • Garay-Sevilla M.E.
      • Gugliucci A.
      Lean adolescents with insulin resistance display higher angiopoietin like protein 3, ApoC-III and chylomicron remnant dyslipidemia.
      ,
      • Wong A.T.
      • Chan D.C.
      • Pang J.
      • Watts G.F.
      • Barrett P.H.
      Plasma apolipoprotein B-48 transport in obese men: a new tracer kinetic study in the postprandial state.
      ,
      • Duez H.
      • Lamarche B.
      • Uffelman K.D.
      • Valero R.
      • Cohn J.S.
      • Lewis G.F.
      Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.
      ,
      • Hogue J.C.
      • Lamarche B.
      • Tremblay A.J.
      • Bergeron J.
      • Gagné C.
      • Couture P.
      Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes.
      ,
      • Padilla N.
      • Maraninchi M.
      • Béliard S.
      • Berthet B.
      • Nogueira J.P.
      • Wolff E.
      • et al.
      Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans.
      ). The finding that insulin resistance is associated with inflated postprandial TG excursions appears to conflict with the previous mentioned positive correlation between SME magnitude and insulin sensitivity. Insulin resistance thus may impair the enterocyte’s ability to siphon dietary fat for storage as CLDs during active absorption. Consequently, a greater proportion of that dietary lipid directly would enter the circulation in the prandial/postprandial period while less would remain within enterocyte CLD to resurface during the next SME.
      Speculation as to the relationship between insulin resistance and dysregulated intestinal lipid metabolism calls up the question of mechanism. Although the intestine is not generally considered a classic insulin target tissue, some evidentiary support exists for a direct effect of insulin on intestinal lipid handling (
      • Veilleux A.
      • Grenier E.
      • Marceau P.
      • Carpentier A.C.
      • Richard D.
      • Levy E.
      Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
      ,
      • Pavlic M.
      • Xiao C.
      • Szeto L.
      • Patterson B.W.
      • Lewis G.F.
      Insulin acutely inhibits intestinal lipoprotein secretion in humans in part by suppressing plasma free fatty acids.
      ). For example, insulin treatment of human fetal jejunal explants decreased the quantity of chylomicrons secreted without affecting their composition (
      • Loirdighi N.
      • Ménard D.
      • Levy E.
      Insulin decreases chylomicron production in human fetal small intestine.
      ). On the other hand, in the setting of preexisting insulin resistance, duodenal explants from humans undergoing biliopancreatic diversion for weight control exhibited increased rates of DNL and apoB-48-TRL secretion in concert with decreased basal AKT phosphorylation versus controls (
      • Veilleux A.
      • Grenier E.
      • Marceau P.
      • Carpentier A.C.
      • Richard D.
      • Levy E.
      Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
      ).
      Several potential mechanisms have been proposed to account for the postulated intestinal resistance to insulin. Unsuppressed FFAs themselves may produce insulin-desensitizing lipotoxic effects (
      • Petersen M.C.
      • Shulman G.I.
      Mechanisms of Insulin Action and Insulin Resistance.
      ), as may their derivatives, notably ceramides (
      • Watt M.J.
      • Barnett A.C.
      • Bruce C.R.
      • Schenk S.
      • Horowitz J.F.
      • Hoy A.J.
      Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide.
      ). The small intestine of patients with the metabolic syndrome may also feature a proinflammatory milieu that, by analogy to the prevailing view in obese adipose tissue, could exacerbate insulin resistance (
      • Veilleux A.
      • Grenier E.
      • Marceau P.
      • Carpentier A.C.
      • Richard D.
      • Levy E.
      Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
      ). Nevertheless, we must also consider the possibility of indirect intestinal effects of insulin resistance elsewhere. Based on the previous discussion of a role for basolateral uptake of plasma FFAs in enterocyte TG synthesis, it follows that exogenous infusion of FFAs during hyperinsulinemic-euglycemic clamp prevents insulin’s suppression of apoB-48 secretion in healthy volunteers (
      • Pavlic M.
      • Xiao C.
      • Szeto L.
      • Patterson B.W.
      • Lewis G.F.
      Insulin acutely inhibits intestinal lipoprotein secretion in humans in part by suppressing plasma free fatty acids.
      ) but not in the chronically hyperlipidemic setting of type 2 diabetes (
      • Nogueira J.P.
      • Maraninchi M.
      • Béliard S.
      • Padilla N.
      • Duvillard L.
      • Mancini J.
      • et al.
      Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes.
      ). Moreover, although surgical treatment of obesity-associated insulin resistance reduced apoB-48-TRL pool size and production rate relative to the preoperative state, even in the setting of constant feeding, this may have been secondary to improvements afield, as apoB-100-TRL pool size decreased to the same extent (
      • Padilla N.
      • Maraninchi M.
      • Béliard S.
      • Berthet B.
      • Nogueira J.P.
      • Wolff E.
      • et al.
      Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans.
      ).
      These direct and indirect effects of insulin resistance on intestinal lipid metabolism are not mutually exclusive and may even reinforce one another. For example, insulin resistance appears to drive up the proportion of chylomicron-TG derived from recirculated (basolaterally reabsorbed) FFAs versus enteral (apically absorbed) FFAs (
      • Shojaee-Moradie F.
      • Ma Y.
      • Lou S.
      • Hovorka R.
      • Umpleby A.M.
      Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol.
      ). Increased intestinal TRL secretion may then provide further substrate for TG lipolysis to FFAs, including with subsequent derivatization to insulin-desensitizing ceramides (
      • Watt M.J.
      • Barnett A.C.
      • Bruce C.R.
      • Schenk S.
      • Horowitz J.F.
      • Hoy A.J.
      Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide.
      ).
      Although such data implicate the intestine in the maintenance—if not also the genesis—of diabetic dyslipidemia, they do not elucidate the enterocellular processes operating between luminal fat input and chylomicron output, particularly as regards the behavior of CLD. As yet, we lack direct human evidence that insulin resistance or diabetes impacts apical or basolateral CLD physiology; circumstantial data generally support the notion but have presented interpretive difficulties. In a study of severely obese patients undergoing weight-loss surgery, TG and apoB-48 levels diverged markedly in blood (both higher) versus in jejunal explants (both lower) in patients with diabetes relative to those without it (
      • Soriguer F.
      • García-Serrano S.
      • Garrido-Sánchez L.
      • Gutierrez-Repiso C.
      • Rojo-Martínez G.
      • Garcia-Escobar E.
      • et al.
      Jejunal wall triglyceride concentration of morbidly obese persons is lower in those with type 2 diabetes mellitus.
      ). These findings could suggest a role for the enterocyte as a buffer against dyslipidemia that fails in the run-up to diabetes (
      • Jacome-Sosa M.
      • Hu Q.
      • Manrique-Acevedo C.M.
      • Phair R.D.
      • Parks E.J.
      Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
      ). Confounding this interpretation, however, the bulk of the stained jejunal-wall neutral lipid resided in the lamina propria, likely in the form of apoB48-TRL, rather than within enterocytes proper; electron microscopic analysis was not presented (
      • Soriguer F.
      • García-Serrano S.
      • Garrido-Sánchez L.
      • Gutierrez-Repiso C.
      • Rojo-Martínez G.
      • Garcia-Escobar E.
      • et al.
      Jejunal wall triglyceride concentration of morbidly obese persons is lower in those with type 2 diabetes mellitus.
      ). Surrogate measures also have not provided straightforward results. For example, small intestine specimens from insulin-resistant humans have shown both increased (
      • Veilleux A.
      • Grenier E.
      • Marceau P.
      • Carpentier A.C.
      • Richard D.
      • Levy E.
      Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
      ,
      • Phillips C.
      • Mullan K.
      • Owens D.
      • Tomkin G.H.
      Intestinal microsomal triglyceride transfer protein in type 2 diabetic and non-diabetic subjects: the relationship to triglyceride-rich postprandial lipoprotein composition.
      ) and decreased (
      • Couture P.
      • Tremblay A.J.
      • Kelly I.
      • Lemelin V.
      • Droit A.
      • Lamarche B.
      Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance.
      ) expression of MTP versus control specimens. Duodenal expressions of several other genes involved in lipoprotein synthesis were lower despite greater apoB-48 (i.e., chylomicron) production rate and pool size in obese humans with versus without insulin resistance (
      • Couture P.
      • Tremblay A.J.
      • Kelly I.
      • Lemelin V.
      • Droit A.
      • Lamarche B.
      Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance.
      ). This dissociation may result from differential impacts of hyperglycemia versus hyperinsulinemia or insulin resistance per se (
      • Drouin-Chartier J.P.
      • Tremblay A.J.
      • Lemelin V.
      • Lamarche B.
      • Couture P.
      Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism.
      ,
      • Xiao C.
      • Dash S.
      • Morgantini C.
      • Lewis G.F.
      Intravenous glucose acutely stimulates intestinal lipoprotein secretion in healthy humans.
      ). A cell-autonomous effect of hyperglycemia itself on human enterocellular lipoprotein production has yet to be demonstrated, but studies of its effects on whole-body apoB-48-TRL kinetics have yielded mixed results (
      • Nogueira J.P.
      • Maraninchi M.
      • Béliard S.
      • Padilla N.
      • Duvillard L.
      • Mancini J.
      • et al.
      Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes.
      • Phillips C.
      • Mullan K.
      • Owens D.
      • Tomkin G.H.
      Intestinal microsomal triglyceride transfer protein in type 2 diabetic and non-diabetic subjects: the relationship to triglyceride-rich postprandial lipoprotein composition.
      ,
      • Xiao C.
      • Dash S.
      • Morgantini C.
      • Lewis G.F.
      Intravenous glucose acutely stimulates intestinal lipoprotein secretion in healthy humans.
      ,
      • Adiels M.
      • Borén J.
      • Caslake M.J.
      • Stewart P.
      • Soro A.
      • Westerbacka J.
      • et al.
      Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia.
      ,
      • Mittendorfer B.
      • Patterson B.W.
      • Klein S.
      • Sidossis L.S.
      VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity.
      ).
      Finally, we once again consider bile acids (BA) given their tight correlation with insulin resistance (
      • Haeusler R.A.
      • Astiarraga B.
      • Camastra S.
      • Accili D.
      • Ferrannini E.
      Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids.
      ,
      • Haeusler R.A.
      • Camastra S.
      • Nannipieri M.
      • Astiarraga B.
      • Castro-Perez J.
      • Xie D.
      • et al.
      Increased bile acid synthesis and impaired bile acid transport in human obesity.
      ,
      • Ferrannini E.
      • Camastra S.
      • Astiarraga B.
      • Nannipieri M.
      • Castro-Perez J.
      • Xie D.
      • et al.
      Increased bile acid synthesis and deconjugation after biliopancreatic diversion.
      ,
      • Legry V.
      • Francque S.
      • Haas J.T.
      • Verrijken A.
      • Caron S.
      • Chávez-Talavera O.
      • et al.
      Bile acid alterations are associated with insulin resistance, but not with NASH, in obese subjects.
      ) and the antidiabetic effects of BA sequestrants (
      • Beysen C.
      • Murphy E.J.
      • Deines K.
      • Chan M.
      • Tsang E.
      • Glass A.
      • et al.
      Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.
      ,
      • Smushkin G.
      • Sathananthan M.
      • Piccinini F.
      • Dalla Man C.
      • Law J.H.
      • Cobelli C.
      • et al.
      The effect of a bile acid sequestrant on glucose metabolism in subjects with type 2 diabetes.
      ). Levels of FGF-19, a classical surrogate of intestinal BA action, are lower despite higher serum bile acid levels in insulin resistance (
      • Schreuder T.C.
      • Marsman H.A.
      • Lenicek M.
      • van Werven J.R.
      • Nederveen A.J.
      • Jansen P.L.
      • et al.
      The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance.
      ,
      • Gerhard G.S.
      • Styer A.M.
      • Wood G.C.
      • Roesch S.L.
      • Petrick A.T.
      • Gabrielsen J.
      • et al.
      A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass.
      ), although the effect of improved insulin resistance on these parameters appears to depend on the treatment modality (
      • Ferrannini E.
      • Camastra S.
      • Astiarraga B.
      • Nannipieri M.
      • Castro-Perez J.
      • Xie D.
      • et al.
      Increased bile acid synthesis and deconjugation after biliopancreatic diversion.
      ,
      • Huang H.H.
      • Lee W.-J.
      • Chen S.-C.
      • Chen T.-F.
      • Lee S.-D.
      • Chen C.-Y.
      Bile acid and fibroblast growth factor 19 regulation in obese diabetics, and non-alcoholic fatty liver disease after sleeve gastrectomy.
      ,
      • Meiring S.
      • Meessen E.C.E.
      • van Baar A.C.G.
      • Holleman F.
      • Nieuwdorp M.
      • Olde Damink S.W.
      • et al.
      Duodenal mucosal resurfacing with GLP-1 receptor agonism increases postprandial unconjugated bile acid in patients with insulin-dependent type 2 diabetes.
      ,
      • van Nierop F.S.
      • Kulik W.
      • Endert E.
      • Schaap F.G.
      • Olde Damink S.W.
      • Romijn J.A.
      • et al.
      Effects of acute dietary weight loss on postprandial plasma bile acid responses in obese insulin resistant subjects.
      ,
      • Sachdev S.
      • Wang Q.
      • Billington C.
      • Connett J.
      • Ahmed L.
      • Inabnet W.
      • et al.
      FGF 19 and bile acids increase following roux-en-Y gastric bypass but not after medical management in patients with type 2 diabetes.
      ,
      • Nemati R.
      • Lu J.
      • Dokpuang D.
      • Booth M.
      • Plank L.D.
      • Murphy R.
      Increased bile acids and FGF19 after sleeve gastrectomy and roux-en-Y gastric bypass correlate with improvement in type 2 diabetes in a randomized trial.
      ).

      Conclusions

      We have attempted to update and streamline a dual-track model of enterocyte lipid handling, with a particular emphasis on human physiology in health and disease. Although others have also proposed elements of a dual-track model (
      • Korbelius M.
      • Vujic N.
      • Sachdev V.
      • Obrowsky S.
      • Rainer S.
      • Gottschalk B.
      • et al.
      ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
      ,
      • Mansbach 2nd, C.M.
      • Dowell R.F.
      Uptake and metabolism of circulating fatty acids by rat intestine.
      ,
      • Storch J.
      • Zhou Y.X.
      • Lagakos W.S.
      Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
      ), it remains largely conceptual due to incomplete understanding of the two tracks and their relationship with one another. Both apical and basolateral tracks can silo their respective fats in distinct cytosolic lipid droplets. Both apical- and basolateral-track CLDs seem capable of participating in similar processes: FAO, structural lipid synthesis, lipoprotein (re)secretion, and storage of other lipid-soluble molecules. However, the ends for which they are employed are where the trail starts to go cold.
      A central question raised by this hypothesis is the extent to which these two tracks interact. That is, do they carry out their activities purely in parallel or do they functionally intersect? We have speculated on interactions between the two tracks, including as an integrated energy-sensing circuit or as a hedge against systemic TG overload. However, these remain hypotheses in want of further testing. Key questions that remain unanswered include the precise mechanism of basolateral FAuptake (i.e., as hydrolyzed FFAs vs. as remnant TRLs), the reason for the apparent dissociation between basolateral track’s β-oxidative potential relative to its demand and why the enterocyte stores fat from each track in distinct CLD.

      Conflict of Interest

      The authors have declared that no conflict of interest exists.

      Acknowledgments

      Images in figures were created with BioRender.com

      Author Contributions

      J. R. C conceptualization; J. R. C writing-original draft; J. R. C. visualization; A. B. K. and R. A. H. writing-review & editing; A. B. K. and R. A. H. funding acquisition.

      Funding and Additional Information

      This work was supported by NIH grants R01DK115825 and R01HL125649 , American Diabetes Association, United States grant 7-20-IBS-130 to RAH and Cystic Fibrosis Foundation, United States (grant Kohan 1810 ), the Rainin Foundation, United States , and the National Institutes of Health, United States ( R01DK118239 , R03DK116011 ) to A. B. K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

      References

        • Ko C.W.
        • Qu J.
        • Black D.D.
        • Tso P.
        Regulation of intestinal lipid metabolism: current concepts and relevance to disease.
        Nat. Rev. Gastroenterol. Hepatol. 2020; 17: 169-183
        • Wit M.
        • Trujillo-Viera J.
        • Strohmeyer A.
        • Klingenspor M.
        • Hankir M.
        • Sumara G.
        When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease.
        EMBO Mol. Med. 2022; 14e14742
        • Xiao C.
        • Stahel P.
        • Nahmias A.
        • Lewis G.F.
        Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization.
        Front. Physiol. 2019; 10: 1604
        • Stone S.J.
        Mechanisms of intestinal triacylglycerol synthesis.
        Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2022; 1867159151
        • Zhang B.
        • Kuipers F.
        • de Boer J.F.
        • Kuivenhoven J.A.
        Modulation of bile acid metabolism to improve plasma lipid and lipoprotein profiles.
        J. Clin. Med. 2021; 11: 4
        • Hoffman S.
        • Alvares D.
        • Adeli K.
        Intestinal lipogenesis: how carbs turn on triglyceride production in the gut.
        Curr. Opin. Clin. Nutr. Metab. Care. 2019; 22: 284-288
        • Xiao C.
        • Stahel P.
        • Lewis G.F.
        Regulation of chylomicron secretion: focus on post-assembly mechanisms.
        Cell Mol. Gastroenterol. Hepatol. 2019; 7: 487-501
        • Cheng S.H.
        • Stanley M.M.
        Secretion of cholesterol by intestinal mucosa in patients with complete common bile duct obstruction.
        Proc. Soc. Exp. Biol. Med. 1959; 101: 223-225
        • Hellman L.
        • Rosenfeld R.S.
        • Eidinoff M.L.
        • Fukushima D.K.
        • Gallagher T.F.
        • Wang C.I.
        • et al.
        Isotopic studies of plasma cholesterol of endogenous and exogenous origins.
        J. Clin. Invest. 1955; 34: 48-60
        • Stanley M.M.
        • Pineda E.P.
        • Cheng S.H.
        Serum cholesterol esters and intestinal cholesterol secretion and absorption in obstructive jaundice due to cancer.
        N. Engl. J. Med. 1959; 261: 368-373
        • Simmonds W.J.
        • Hofmann A.F.
        • Theodor E.
        Absorption of cholesterol from a micellar solution: intestinal perfusion studies in man.
        J. Clin. Invest. 1967; 46: 874-890
        • Jakulj L.
        • van Dijk T.H.
        • de Boer J.F.
        • Kootte R.S.
        • Schonewille M.
        • Paalvast Y.
        • et al.
        Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion.
        Cell Metab. 2016; 24: 783-794
        • Korbelius M.
        • Vujic N.
        • Sachdev V.
        • Obrowsky S.
        • Rainer S.
        • Gottschalk B.
        • et al.
        ATGL/CGI-58-dependent hydrolysis of a lipid storage pool in murine enterocytes.
        Cell Rep. 2019; 28: 1923-1934.e4
        • Li D.
        • Rodia C.N.
        • Johnson Z.K.
        • Bae M.
        • Muter A.
        • Heussinger A.E.
        • et al.
        Intestinal basolateral lipid substrate transport is linked to chylomicron secretion and is regulated by apoC-III.
        J. Lipid Res. 2019; 60: 1503-1515
        • Mansbach 2nd, C.M.
        • Dowell R.F.
        Uptake and metabolism of circulating fatty acids by rat intestine.
        Am. J. Physiol. 1992; 263: G927-G933
        • Storch J.
        • Zhou Y.X.
        • Lagakos W.S.
        Metabolism of apical versus basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine.
        J. Lipid Res. 2008; 49: 1762-1769
        • Gangl A.
        • Ockner R.K.
        Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.
        J. Clin. Invest. 1975; 55: 803-813
        • Mansbach 2nd, C.M.
        • Dowell R.F.
        Role of the intestine in chylomicron remnant clearance.
        Am. J. Physiol. 1995; 269: G144-G152
        • Soued M.
        • Mansbach C.M.
        2nd, Chylomicron remnant uptake by enterocytes is receptor dependent.
        Am. J. Physiol. 1996; 270: G203-G212
        • Cohn J.S.
        • McNamara J.R.
        • Krasinski S.D.
        • Russell R.M.
        • Schaefer E.J.
        Role of triglyceride-rich lipoproteins from the liver and intestine in the etiology of postprandial peaks in plasma triglyceride concentration.
        Metabolism. 1989; 38: 484-490
        • Evans K.
        • Kuusela P.J.
        • Cruz M.L.
        • Wilhelmova I.
        • Fielding B.A.
        • Frayn K.N.
        Rapid chylomicron appearance following sequential meals: effects of second meal composition.
        Br. J. Nutr. 1998; 79: 425-429
        • Fielding B.A.
        • Callow J.
        • Owen R.M.
        • Samra J.S.
        • Matthews D.R.
        • Frayn K.N.
        Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals.
        Am. J. Clin. Nutr. 1996; 63: 36-41
        • Williams C.M.
        • Moore F.
        • Morgan L.
        • Wright J.
        Effects of n-3 fatty acids on postprandial triacylglycerol and hormone concentrations in normal subjects.
        Br. J. Nutr. 1992; 68: 655-666
        • Jackson K.G.
        • Robertson M.D.
        • Fielding B.A.
        • Frayn K.N.
        • Williams C.M.
        Second meal effect: modified sham feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal.
        Br. J. Nutr. 2001; 85: 149-156
        • Jacome-Sosa M.
        • Hu Q.
        • Manrique-Acevedo C.M.
        • Phair R.D.
        • Parks E.J.
        Human intestinal lipid storage through sequential meals reveals faster dinner appearance is associated with hyperlipidemia.
        JCI Insight. 2021; 6e148378
        • Silva K.D.
        • Wright J.W.
        • Williams C.M.
        • Lovegrove J.A.
        Meal ingestion provokes entry of lipoproteins containing fat from the previous meal: possible metabolic implications.
        Eur. J. Nutr. 2005; 44: 377-383
        • Heath R.B.
        • Karpe F.
        • Milne R.W.
        • Burdge G.C.
        • Wootton S.A.
        • Frayn K.N.
        Dietary fatty acids make a rapid and substantial contribution to VLDL-triacylglycerol in the fed state.
        Am. J. Physiol. Endocrinol. Metab. 2007; 292: E732-E739
        • Robertson M.D.
        • Parkes M.
        • Warren B.F.
        • Ferguson D.J.
        • Jackson K.G.
        • Jewell D.P.
        • et al.
        Mobilisation of enterocyte fat stores by oral glucose in humans.
        Gut. 2003; 52: 834-839
        • Hodson L.
        • McQuaid S.E.
        • Karpe F.
        • Frayn K.N.
        • Fielding B.A.
        Differences in partitioning of meal fatty acids into blood lipid fractions: a comparison of linoleate, oleate, and palmitate.
        Am. J. Physiol. Endocrinol. Metab. 2009; 296: E64-E71
        • Chavez-Jauregui R.N.
        • Mattes R.D.
        • Parks E.J.
        Dynamics of fat absorption and effect of sham feeding on postprandial lipema.
        Gastroenterology. 2010; 139: 1538-1548
        • Xiao C.
        • Stahel P.
        • Carreiro A.L.
        • Hung Y.H.
        • Dash S.
        • Bookman I.
        • et al.
        Oral Glucose Mobilizes Triglyceride Stores From the Human Intestine.
        Cell Mol. Gastroenterol. Hepatol. 2019; 7: 313-337
        • Zierenberg O.
        • Grundy S.M.
        Intestinal absorption of polyenephosphatidylcholine in man.
        J. Lipid Res. 1982; 23: 1136-1142
        • Werner A.
        • Havinga R.
        • Perton F.
        • Kuipers F.
        • Verkade H.J.
        Lymphatic chylomicron size is inversely related to biliary phospholipid secretion in mice.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2006; 290: G1177-G1185
        • Tso P.
        • Kendrick H.
        • Balint J.A.
        • Simmonds W.J.
        Role of biliary phosphatidylcholine in the absorption and transport of dietary triolein in the rat.
        Gastroenterology. 1981; 80: 60-65
        • Fiamoncini J.
        • Yiorkas A.M.
        • Gedrich K.
        • Rundle M.
        • Alsters S.I.
        • Roeselers G.
        • et al.
        Determinants of postprandial plasma bile acid kinetics in human volunteers.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2017; 313: G300-G312
        • Liddle R.A.
        • Goldfine I.D.
        • Rosen M.S.
        • Taplitz R.A.
        • Williams J.A.
        Cholecystokinin bioactivity in human plasma. molecular forms, responses to feeding, and relationship to gallbladder contraction.
        J. Clin. Invest. 1985; 75: 1144-1152
        • Hofmann A.F.
        The continuing importance of bile acids in liver and intestinal disease.
        Arch. Intern. Med. 1999; 159: 2647-2658
        • Shrivastava B.K.
        • Redgrave T.G.
        • Simmonds W.J.
        The source of endogenous lipid in the thoracic duct lymph of fasting rats.
        Q. J. Exp. Physiol. Cogn. Med. Sci. 1967; 52: 305-312
        • Martins I.J.
        • Sainsbury A.J.
        • Mamo J.C.
        • Redgrave T.G.
        Lipid and apolipoprotein B48 transport in mesenteric lymph and the effect of hyperphagia on the clearance of chylomicron-like emulsions in insulin-deficient rats.
        Diabetologia. 1994; 37: 238-246
        • Karupaiah T.
        • Sundram K.
        Effects of stereospecific positioning of fatty acids in triacylglycerol structures in native and randomized fats: a review of their nutritional implications.
        Nutr. Metab. (Lond). 2007; 4: 16
        • Björnson E.
        • Packard C.J.
        • Adiels M.