Thematic Reviews
Deep-lipidotyping by mass spectrometry: recent technical advances and applications
In-depth structural characterization of lipids is an essential component of lipidomics. There has been a rapid expansion of mass spectrometry methods that are capable of resolving lipid isomers at various structural levels over the past decade. These developments finally make deep-lipidotyping possible, which provides new means to study lipid metabolism and discover new lipid biomarkers. In this review, we discuss recent advancements in tandem mass spectrometry (MS/MS) methods for identification of complex lipids beyond the species (known headgroup information) and molecular species (known chain composition) levels.Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4
Lipids play essential roles in maintaining cell structure and function by modulating membrane fluidity and cell signaling. The fatty acid elongase-4 (ELOVL4) protein, expressed in retina, brain, Meibomian glands, skin, testes and sperm, is an essential enzyme that mediates tissue-specific biosynthesis of both VLC-PUFA and VLC-saturated fatty acids (VLC-SFA). These fatty acids play critical roles in maintaining retina and brain function, neuroprotection, skin permeability barrier maintenance, and sperm function, among other important cellular processes.Existing and emerging therapies for the treatment of familial hypercholesterolemia
Familial hypercholesterolemia (FH), an autosomal dominant disorder of LDL metabolism that is characterized by elevated LDL-cholesterol, is commonly encountered in patients with atherosclerotic coronary heart disease. Combinations of cholesterol-lowering therapies are often used to lower LDL-cholesterol in patients with FH; however, current treatment goals for LDL-cholesterol are rarely achieved in patients with homozygous FH (HoFH) and are difficult to achieve in patients with heterozygous FH (HeFH).Lipoprotein metabolism in familial hypercholesterolemia
Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (LDLR/APOB/PCSK9/LDLRAP1) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway.The lipidome in nonalcoholic fatty liver disease: actionable targets
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. Recent technological advances, combined with OMICs experiments and explorations involving different biological samples, have uncovered vital aspects of NAFLD biology. In this review, we summarize recent work by our group and others that expands what is known about the role of lipidome in NAFLD pathogenesis. We discuss how pathway and enrichment analyses were performed by integrating a list of query metabolites derived from text-mining existing NAFLD-lipidomics studies, resulting in the identification of nine Kyoto Encyclopedia of Genes and Genomes dysregulated pathways, including biosynthesis of unsaturated fatty acids, butanoate metabolism, synthesis and degradation of ketone bodies, sphingolipid, arachidonic acid and pyruvate metabolism, and numerous nonsteroidal antiinflammatory drug pathways predicted from The Small Molecule Pathway Database.The lipid biology of sepsis
Sepsis, defined as the dysregulated immune response to an infection leading to organ dysfunction, is one of the leading causes of mortality around the globe. Despite the significant progress in delineating the underlying mechanisms of sepsis pathogenesis, there are currently no effective treatments or specific diagnostic biomarkers in the clinical setting. The perturbation of cell signaling mechanisms, inadequate inflammation resolution, and energy imbalance, all of which are altered during sepsis, are also known to lead to defective lipid metabolism.Clinical lipidomics: realizing the potential of lipid profiling
Dysregulation of lipid metabolism plays a major role in the etiology and sequelae of inflammatory disorders, cardiometabolic and neurological diseases, and several forms of cancer. Recent advances in lipidomic methodology allow comprehensive lipidomic profiling of clinically relevant biological samples, enabling researchers to associate lipid species and metabolic pathways with disease onset and progression. The resulting data serve not only to advance our fundamental knowledge of the underlying disease process but also to develop risk assessment models to assist in the diagnosis and management of disease.The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer
In 2003, the sequences of mammalian proprotein convertase subtilisin/kexin type 9 (PCSK9) were reported. Radiolabeling pulse-chase analyses demonstrated that PCSK9 was synthesized as a precursor (proPCSK9) that undergoes autocatalytic cleavage in the endoplasmic reticulum into PCSK9, which is then secreted as an inactive enzyme in complex with its inhibitory prodomain. Its high mRNA expression in liver hepatocytes and its gene localization on chromosome 1p32, a third locus associated with familial hypercholesterolemia, other than LDLR or APOB, led us to identify three patient families expressing the PCSK9 variants S127R or F216L.Genetic testing for familial hypercholesterolemia—past, present, and future
In the early 1980s, the Nobel Prize winning cellular and molecular work of Mike Brown and Joe Goldstein led to the identification of the LDL receptor gene as the first gene where mutations cause the familial hypercholesterolemia (FH) phenotype. We now know that autosomal dominant monogenic FH can be caused by pathogenic variants of three additional genes (APOB/PCSK9/APOE) and that the plasma LDL-C concentration and risk of premature coronary heart disease differs according to the specific locus and associated molecular cause.Fatty acid oxidation and photoreceptor metabolic needs
Photoreceptors have high energy demands and a high density of mitochondria that produce ATP through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for CNS brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS.Bisretinoid phospholipid and vitamin A aldehyde: shining a light
Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity.Signaling roles of phosphoinositides in the retina
The field of phosphoinositide signaling has expanded significantly in recent years. Phosphoinositides (also known as phosphatidylinositol phosphates or PIPs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind phosphoinositides and are recruited to cell membranes. Through the activities of phosphoinositide kinases and phosphoinositide phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule, phosphatidylinositol.Retinoids in the visual cycle: role of the retinal G protein-coupled receptor
Driven by the energy of a photon, the visual pigments in rod and cone photoreceptor cells isomerize 11-cis-retinal to the all-trans configuration. This photochemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a visual signal to the brain and leaves the opsins insensitive to further light stimulation. For the eye to restore light sensitivity, opsins require recharging with 11-cis-retinal. This trans-cis back conversion is achieved through a series of enzymatic reactions composing the retinoid (visual) cycle.Lipid conformational order and the etiology of cataract and dry eye
Lens and tear film lipids are as unique as the systems they reside in. The major lipid of the human lens is dihydrosphingomylein, found in quantity only in the lens. The lens contains a cholesterol to phospholipid molar ratio as high as 10:1, more than anywhere else in the body. Lens lipids contribute to maintaining lens clarity, and alterations in lens lipid composition due to age are likely to contribute to cataract. Lens lipid composition reflects adaptations to the unique characteristics of the lens: no turnover of lens lipids or proteins; the lowest amount of oxygen of any tissue; and contains almost no intracellular organelles.Docosanoid signaling modulates corneal nerve regeneration: effect on tear secretion, wound healing, and neuropathic pain
The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using ω-3 supplementation show unclear and sometimes negative results.The emerging roles of the macular pigment carotenoids throughout the lifespan and in prenatal supplementation
Since the publication of the Age-Related Eye Disease Study 2 (AREDS2) in 2013, the macular pigment carotenoids lutein (L) and zeaxanthin (Z) have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration.Sphingolipids as critical players in retinal physiology and pathology
Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases.Cholesterol homeostasis in the vertebrate retina: biology and pathobiology
Cholesterol is a quantitatively and biologically significant constituent of all mammalian cell membrane, including those that comprise the retina. Retinal cholesterol homeostasis entails the interplay between de novo synthesis, uptake, intraretinal sterol transport, metabolism, and efflux. Defects in these complex processes are associated with several congenital and age-related disorders of the visual system. Herein, we provide an overview of the following topics: (a) cholesterol synthesis in the neural retina; (b) lipoprotein uptake and intraretinal sterol transport in the neural retina and the retinal pigment epithelium (RPE); (c) cholesterol efflux from the neural retina and the RPE; and (d) biology and pathobiology of defects in sterol synthesis and sterol oxidation in the neural retina and the RPE.Lipid metabolism dysregulation in diabetic retinopathy
Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of diabetic complications, including diabetic retinopathy (DR). This review article provides an overview of the results of clinical trials evaluating the potential benefits of lipid-lowering drugs, such as fibrates, omega-3 fatty acids, and statins, for the prevention and treatment of DR. Although several clinical trials demonstrated that treatment with fibrates leads to improvement of DR, there is a dissociation between the protective effects of fibrates in the retina, and the intended blood lipid classes, including plasma triglycerides, total cholesterol, or HDL:LDL cholesterol ratio.FH through the retrospectoscope
After training as a gastroenterologist in the UK, the author became interested in lipidology while he was a research fellow in the USA and switched careers after returning home. Together with Nick Myant, he introduced the use of plasma exchange to treat familial hypercholesterolemia (FH) homozygotes and undertook non-steady state studies of LDL kinetics, which showed that the fractional catabolic rate of LDL remained constant irrespective of pool size. Subsequent steady-state turnover studies showed that FH homozygotes had an almost complete lack of receptor-mediated LDL catabolism, providing in vivo confirmation of the Nobel Prize-winning discovery by Goldstein and Brown that LDL receptor dysfunction was the cause of FH.Overview of how N32 and N34 elovanoids sustain sight by protecting retinal pigment epithelial cells and photoreceptors
The essential fatty acid DHA (22:6, omega-3 or n-3) is enriched in and required for the membrane biogenesis and function of photoreceptor cells (PRCs), synapses, mitochondria, etc. of the CNS. PRC DHA becomes an acyl chain at the sn-2 of phosphatidylcholine, amounting to more than 50% of the PRC outer segment phospholipids, where phototransduction takes place. Very long chain PUFAs (n-3, ≥ 28 carbons) are at the sn-1 of this phosphatidylcholine molecular species and interact with rhodopsin. PRC shed their tips (DHA-rich membrane disks) daily, which in turn are phagocytized by the retinal pigment epithelium (RPE), where DHA is recycled back to PRC inner segments to be used for the biogenesis of new photoreceptor membranes.Introduction to the Thematic Review Series: Seeing 2020: lipids and lipid-soluble molecules in the eye
In 2010, this journal published a series of review articles in a Thematic Issue entitled “Lipids and Lipid Metabolism in the Eye.” Over the ensuing decade, a number of significant advances have been made that are pertinent to this broad topic, which prompted us to launch a follow-up Thematic Issue to present updates on several of the topics reviewed in that prior issue as well as to expand into new areas that previously had not been addressed. In addition to considering the conventional classes of lipids (e.g., glycerophospholipids, sphingolipids, fatty acids, and sterols), we also wanted to address some key lipid-soluble molecules (e.g., retinoids, bisretinoids, and carotenoids) that play important physiological roles in ocular tissues.Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases: Thematic Review Series: Biology of Lipid Rafts
Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators.The ins and outs of lipid rafts: functions in intracellular cholesterol homeostasis, microparticles, and cell membranes: Thematic Review Series: Biology of Lipid Rafts
Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts.Lipid rafts and pathogens: the art of deception and exploitation: Thematic Review Series: Biology of Lipid Rafts
Lipid rafts, solid regions of the plasma membrane enriched in cholesterol and glycosphingolipids, are essential parts of a cell. Functionally, lipid rafts present a platform that facilitates interaction of cells with the outside world. However, the unique properties of lipid rafts required to fulfill this function at the same time make them susceptible to exploitation by pathogens. Many steps of pathogen interaction with host cells, and sometimes all steps within the entire lifecycle of various pathogens, rely on host lipid rafts.Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases: Thematic Review Series: Biology of Lipid Rafts
Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type.Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: Thematic Review Series: Biology of Lipid Rafts
Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts.Lipid rafts in glial cells: role in neuroinflammation and pain processing: Thematic Review Series: Biology of Lipid Rafts
Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways.Lipid rafts as a therapeutic target: Thematic Review Series: Biology of Lipid Rafts
Lipid rafts regulate the initiation of cellular metabolic and signaling pathways by organizing the pathway components in ordered microdomains on the cell surface. Cellular responses regulated by lipid rafts range from physiological to pathological, and the success of a therapeutic approach targeting “pathological” lipid rafts depends on the ability of a remedial agent to recognize them and disrupt pathological lipid rafts without affecting normal raft-dependent cellular functions. In this article, concluding the Thematic Review Series on Biology of Lipid Rafts, we review current experimental therapies targeting pathological lipid rafts, including examples of inflammarafts and clusters of apoptotic signaling molecule-enriched rafts.Contributions of innate type 2 inflammation to adipose function
A critical contributor to the health consequences of the obesity epidemic is dysregulated adipose tissue (AT) homeostasis. While white, brown, and beige AT function is altered in obesity-related disease, white AT is marked by progressive inflammation and adipocyte dysfunction and has been the focus of extensive “immunometabolism” research in the past decade. The exact triggering events initiating and sustaining AT inflammation are still under study, but it has been shown that reducing inflammation improves insulin action in AT.Determinants of body fat distribution in humans may provide insight about obesity-related health risks
Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks.Muscle and adipose tissue insulin resistance: malady without mechanism?
Insulin resistance is a major risk factor for numerous diseases, including type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of “common” insulin resistance. Despite considerable effort, the mechanisms that contribute to common insulin resistance are not resolved. There is universal agreement that extracellular perturbations, such as nutrient excess, hyperinsulinemia, glucocorticoids, or inflammation, trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells.Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication
The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process.Membrane lipids define small extracellular vesicle subtypes secreted by mesenchymal stromal cells
The therapeutic efficacy of mesenchymal stromal cells (MSCs), multipotent progenitor cells, is attributed to small (50–200 nm) extracellular vesicles (EVs). The presence of a lipid membrane differentiates exosomes and EVs from other macromolecules. Analysis of this lipid membrane revealed three distinct small MSC EV subtypes, each with a differential affinity for cholera toxin B chain (CTB), annexin V (AV), and Shiga toxin B chain (ST) that bind GM1 ganglioside, phosphatidylserine, and globotriaosylceramide, respectively.The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease
Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4-, and 3- positions. Human PI 5-phosphatases belong to a family of 10 members. Except for inositol polyphosphate 5-phosphatase A, they all catalyze the dephosphorylation of PI(4,5)P2 and/or PI(3,4,5)P3 at the 5- position. PI 5-phosphatases thus directly control the levels of PI(3,4,5)P3 and participate in the fine-tuning regulatory mechanisms of PI(3,4)P2 and PI(4,5)P2.GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer
GOLPH3 is a peripheral membrane protein localized to the Golgi and its vesicles, but its purpose had been unclear. We found that GOLPH3 binds specifically to the phosphoinositide phosphatidylinositol(4)phosphate [PtdIns(4)P], which functions at the Golgi to promote vesicle exit for trafficking to the plasma membrane. PtdIns(4)P is enriched at the trans-Golgi and so recruits GOLPH3. Here, a GOLPH3 complex is formed when it binds to myosin18A (MYO18A), which binds F-actin. This complex generates a pulling force to extract vesicles from the Golgi; interference with this GOLPH3 complex results in dramatically reduced vesicle trafficking.Signaling through non-membrane nuclear phosphoinositide binding proteins in human health and disease
Phosphoinositide membrane signaling is critical for normal physiology, playing well-known roles in diverse human pathologies. The basic mechanisms governing phosphoinositide signaling within the nucleus, however, have remained deeply enigmatic owing to their presence outside the nuclear membranes. Over 40% of nuclear phosphoinositides can exist in this non-membrane state, held soluble in the nucleoplasm by nuclear proteins that remain largely unidentified. Recently, two nuclear proteins responsible for solubilizing phosphoinositides were identified, steroidogenic factor-1 (SF-1; NR5A1) and liver receptor homolog-1 (LRH-1; NR5A2), along with two enzymes that directly remodel these phosphoinositide/protein complexes, phosphatase and tensin homolog (PTEN; MMAC) and inositol polyphosphate multikinase (IPMK; ipk2).VPS34 complexes from a structural perspective
VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the phosphoinositide 3-kinase (PI3K) family. VPS34 has a simpler domain organization than class I PI3Ks, which belies the complexity of its quaternary organization, with the enzyme always functioning within larger assemblies. PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II.The interface between phosphatidylinositol transfer protein function and phosphoinositide signaling in higher eukaryotes
Phosphoinositides are key regulators of a large number of diverse cellular processes that include membrane trafficking, plasma membrane receptor signaling, cell proliferation, and transcription. How a small number of chemically distinct phosphoinositide signals are functionally amplified to exert specific control over such a diverse set of biological outcomes remains incompletely understood. To this end, a novel mechanism is now taking shape, and it involves phosphatidylinositol (PtdIns) transfer proteins (PITPs).Nuclear phospholipase C isoenzyme imbalance leads to pathologies in brain, hematologic, neuromuscular, and fertility disorders
Phosphoinositide-specific phospholipases C (PI-PLCs) are involved in signaling pathways related to critical cellular functions, such as cell cycle regulation, cell differentiation, and gene expression. Nuclear PI-PLCs have been studied as key enzymes, molecular targets, and clinical prognostic/diagnostic factors in many physiopathologic processes. Here, we summarize the main studies about nuclear PI-PLCs, specifically, the imbalance of isozymes such as PI-PLCβ1 and PI-PLCζ, in cerebral, hematologic, neuromuscular, and fertility disorders.Phosphoinositides in the kidney
Phosphoinositides (PIs) play pivotal roles in the regulation of many biological processes. The quality and quantity of PIs is regulated in time and space by the activity of PI kinases and PI phosphatases. The number of PI-metabolizing enzymes exceeds the number of PIs with, in many cases, more than one enzyme controlling the same biochemical step. This would suggest that the PI system has an intrinsic ability to buffer and compensate for the absence of a specific enzymatic activity. However, there are several examples of severe inherited human diseases caused by mutations in one of the PI enzymes, although other enzymes with the same activity are fully functional.Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology
Exosomes are a type of extracellular vesicle released from cells after fusion of multivesicular bodies with the plasma membrane. These vesicles are often enriched in cholesterol, SM, glycosphingolipids, and phosphatidylserine. Lipids not only have a structural role in exosomal membranes but also are essential players in exosome formation and release to the extracellular environment. Our knowledge about the importance of lipids in exosome biology is increasing due to recent technological developments in lipidomics and a stronger focus on the biological functions of these molecules.Thematic Review Series: Exosomes and Microvesicles: Lipids as Key Components of their Biogenesis and Functions, Cholesterol and the journey of extracellular vesicles
Eukaryotic cells employ distinct means to release specific signals and material. Research within the last decade has identified different types of membrane-enclosed structures collectively called extracellular vesicles (EVs) as one of them. EVs fall into two categories depending on their subcellular origin. Exosomes are generated within the endosomal system and reach the extracellular space upon fusion of multivesicular bodies. Microvesicles or microparticles are generated by shedding of the plasma membrane.Thematic Review Series: Exosomes and Microvesicles: Lipids as Key Components of their Biogenesis and Functions Extracellular vesicles and their content in bioactive lipid mediators: more than a sack of microRNA
Extracellular vesicles (EVs), such as exosomes and microvesicles, are small membrane-bound vesicles released by cells under various conditions. In a multitude of physiological and pathological conditions, EVs contribute to intercellular communication by facilitating exchange of material between cells. Rapidly growing interest is aimed at better understanding EV function and their use as biomarkers. The vast EV cargo includes cytokines, growth factors, organelles, nucleic acids (messenger and micro RNA), and transcription factors.Thematic Review Series: Living History of Lipids The arachidonic acid monooxygenase: from biochemical curiosity to physiological/pathophysiological significance
The initial studies of the metabolism of arachidonic acid (AA) by the cytochrome P450 (P450) hemeproteins sought to: a) elucidate the roles for these enzymes in the metabolism of endogenous pools of the FA, b) identify the P450 isoforms involved in AA epoxidation and ω/ω-1 hydroxylation, and c) explore the biological activities of their metabolites. These early investigations provided a foundation for subsequent efforts to establish the physiological relevance of the AA monooxygenase and its contributions to the pathophysiology of, for example, cancer, diabetes, hypertension, inflammation, nociception, and vascular disease.A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite
Cancer cells must adapt their metabolism in order to meet the energy requirements for cell proliferation, survival in nutrient-deprived environments, and dissemination. In particular, FA metabolism is emerging as a critical process for tumors. FA metabolism can be modulated through intrinsic changes in gene expression or signaling between tumor cells and also in response to signals from the surrounding microenvironment. Among these signals, extracellular vesicles (EVs) could play an important role in FA metabolism remodeling.Phospholipase D and phosphatidic acid in the biogenesis and cargo loading of extracellular vesicles: Thematic Review Series: Exosomes and Microvesicles: Lipids as Key Components of their Biogenesis and Functions
Extracellular vesicles released by viable cells (exosomes and microvesicles) have emerged as important organelles supporting cell-cell communication. Because of their potential therapeutic significance, important efforts are being made toward characterizing the contents of these vesicles and the mechanisms that govern their biogenesis. It has been recently demonstrated that the lipid modifying enzyme, phospholipase D (PLD)2, is involved in exosome production and acts downstream of the small GTPase, ARF6.Extracellular vesicles: lipids as key components of their biogenesis and functions
Intercellular communication has been known for decades to involve either direct contact between cells or to operate via circulating molecules, such as cytokines, growth factors, or lipid mediators. During the last decade, we have begun to appreciate the increasing importance of intercellular communication mediated by extracellular vesicles released by viable cells either from plasma membrane shedding (microvesicles, also named microparticles) or from an intracellular compartment (exosomes). Exosomes and microvesicles circulate in all biological fluids and can trigger biological responses at a distance.Plant lipid transfer proteins: are we finally closing in on the roles of these enigmatic proteins?
The nonspecific lipid transfer proteins (LTPs) are small compact proteins folded around a tunnel-like hydrophobic cavity, making them suitable for lipid binding and transport. LTPs are encoded by large gene families in all land plants, but they have not been identified in algae or any other organisms. Thus, LTPs are considered key proteins for plant survival on and colonization of land. LTPs are abundantly expressed in most plant tissues, both above and below ground. They are usually localized to extracellular spaces outside the plasma membrane.Role of lipid transfer proteins in loading CD1 antigen-presenting molecules
Research to connect lipids with immunology is growing, but details about the specific roles of lipid transfer proteins (LTPs) in antigen presentation remain unclear. A single class of major histocompatibility class-like molecules, called CD1 molecules, can present lipids and glycolipids to the immune system. These molecules all have a common hydrophobic antigen-binding groove. The loading of this groove with various lipids throughout the life of a CD1 molecule defines the immune recognition of lipids by T cells.Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles
Extracellular vesicles (EVs) are membrane vesicles released by both eukaryotic and prokaryotic cells; they not only serve physiological functions, such as disposal of cellular components, but also play pathophysiologic roles in inflammatory and degenerative diseases. Common molecular mechanisms for EV biogenesis are evident in different cell biological contexts across eukaryotic phyla, and inhibition of this biogenesis may provide an avenue for therapeutic research. The involvement of sphingolipids (SLs) and their enzymes on EV biogenesis and release has not received much attention in current research.Lipid transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sites
The endoplasmic reticulum (ER) is the main center for the synthesis of various lipid types in cells, and newly synthesized lipids are delivered from the ER to other organelles. In the past decade, various lipid transfer proteins (LTPs) have been recognized as mediators of lipid transport from the ER to other organelles; inter-organelle transport occurs at membrane contact sites (MCSs) and in a nonvesicular manner. Although the intermembrane transfer reaction catalyzed by LTPs is an equilibrium reaction, various types of newly synthesized lipids are transported unidirectionally in cells.The role of lipoprotein (a) in chronic kidney disease: Thematic Review Series: Lipoprotein (a): Coming of Age at Last
Lipoprotein (a) [Lp(a)] and its measurement, structure and function, the impact of ethnicity and environmental factors, epidemiological and genetic associations with vascular disease, and new prospects in drug development have been extensively examined throughout this Thematic Review Series on Lp(a). Studies suggest that the kidney has a role in Lp(a) catabolism, and that Lp(a) levels are increased in association with kidney disease only for people with large apo(a) isoforms. By contrast, in those patients with large protein losses, as in the nephrotic syndrome and continuous ambulatory peritoneal dialysis, Lp(a) is increased irrespective of apo(a) isoform size.Is ABCA1 a lipid transfer protein?
ABCA1 functions as a lipid transporter because it mediates the transfer of cellular phospholipid (PL) and free (unesterified) cholesterol (FC) to apoA-I and related proteins present in the extracellular medium. ABCA1 is a membrane PL translocase and its enzymatic activity leads to transfer of PL molecules from the cytoplasmic leaflet to the exofacial leaflet of a cell plasma membrane (PM). The presence of active ABCA1 in the PM promotes binding of apoA-I to the cell surface. About 10% of this bound apoA-I interacts directly with ABCA1 and stabilizes the transporter.Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis
Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development in humans; however, we still do not quite understand the mechanisms. In mouse models, PLTP overexpression induces atherosclerosis, while its deficiency reduces it. Thus, mouse models were used to explore the mechanisms. In this review, I summarize the major progress made in the PLTP research field and emphasize its impact on lipoprotein metabolism and atherosclerosis, as well as its regulation.Cholesteryl ester transfer protein and its inhibitors
Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD.Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization
The widely expressed transmembrane glycoprotein, cluster of differentiation 36 (CD36), a scavenger receptor class B protein (SR-B2), serves many functions in lipid metabolism and signaling. Here, we review CD36's role in facilitating cellular long-chain fatty acid uptake across the plasma membrane, particularly in heart and skeletal muscles. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein, and is an intracellular docking site for cytoplasmic fatty acid-binding protein.Thematic Review Series: Lipid Transfer Proteins Scavenger receptor B type 1: expression, molecular regulation, and cholesterol transport function
Cholesterol is required for maintenance of plasma membrane fluidity and integrity and for many cellular functions. Cellular cholesterol can be obtained from lipoproteins in a selective pathway of HDL-cholesteryl ester (CE) uptake without parallel apolipoprotein uptake. Scavenger receptor B type 1 (SR-B1) is a cell surface HDL receptor that mediates HDL-CE uptake. It is most abundantly expressed in liver, where it provides cholesterol for bile acid synthesis, and in steroidogenic tissues, where it delivers cholesterol needed for storage or steroidogenesis in rodents.Lipid transfer proteins in the assembly of apoB-containing lipoproteins
A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum (ER) and is dependent on lipid resynthesis in the ER and on a chaperone, namely, microsomal triglyceride transfer protein (MTTP).Historical perspective: phosphatidylserine and phosphatidylethanolamine from the 1800s to the present
This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), including the ether lipids. In addition, the article describes the biosynthetic pathways for these phospholipids and how these pathways were elucidated. Several unique functions of PS and PE in mammalian cells in addition to their ability to define physical properties of membranes are discussed. For example, the translocation of PS from the inner to the outer leaflet of the plasma membrane of cells occurs during apoptosis and during some other specific physiological processes, and this translocation is responsible for profound life-or-death events.Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols
The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body.
