Thematic review series: Patient-Oriented Research. Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein patterns

      In general, under isoweight conditions, different types of dietary protein or individual amino acids have little effect on lipoprotein patterns. Dietary carbohydrate tends to increase plasma triglyceride when it displaces fat, accompanied by a decrease in HDL cholesterol concentrations. Potential differential effects of types of carbohydrate are difficult to assess because of differences in rates of absorption and confounding of dietary fiber. Saturated fatty acids increase LDL and HDL cholesterol, whereas trans fatty acids increase LDL but not HDL cholesterol. Unsaturated fatty acids decrease LDL and HDL cholesterol, polyunsaturated more so than monounsaturated. There has been considerable interest in the potential benefit of major shifts in dietary macronutrients on weight loss and lipoprotein patterns. Short-term data favor substituting protein and fat for carbohydrate, whereas long-term data have failed to show a benefit for weight loss. During an active weight loss period low-carbohydrate diets more favorably affect triglyceride and HDL and less favorably affect LDL cholesterol concentrations. Additional efforts need to be focused on gaining a better understanding of the effect of dietary macronutrient profiles on established and emerging cardiovascular disease risk factors, mechanisms for changes observed and contributors to individual variability. Such data are needed to allow reassessment and, if necessary, modification of current recommendations.
      Dietary fat, carbohydrate, and protein are the primary energy-containing macronutrients consumed on a routine basis by humans. Dietary alcohol provides a unique category of energy and will not be considered in this review. Trendy weight loss diets that have flourished during the past decade have resulted in the generation of a considerable amount of data on how major shifts in the macronutrient content of the diet affect plasma lipoprotein patterns. These data can be used to inform dietary recommendations to minimize the risk of developing cardiovascular disease (CVD).
      It is difficult to consider the independent effect of dietary fat, carbohydrate, or protein on plasma lipoprotein patterns because, in each case, in addition to contributing unique essential and nonessential nutrients, the macronutrients also contribute the majority of metabolic energy to sustain life. To maintain a stable body weight, if the intake of one macronutrient is increased or decreased, there needs to be a compensatory adjustment in one or both of the other macronutrients. Under these circumstances, the effect observed on plasma lipoprotein patterns can be attributable to either the addition of one macronutrient or the reduction of the other(s). If a single macronutrient is increased or decreased without compensatory adjustments in the amount of the other macronutrients, body weight will change and any effect on plasma lipoprotein patterns will result from changes induced by weight loss or gain, a shift in the relative energy distribution of each macronutrient, or some combination thereof (
      • Kasim-Karakas S.E.
      • Almario R.U.
      • Mueller W.M.
      • Peerson J.
      Changes in plasma lipoproteins during low-fat, high-carbohydrate diets: effects of energy intake.
      ,
      • Lichtenstein A.H.
      • Ausman L.M.
      • Carrasco W.
      • Jenner J.L.
      • Ordovas J.M.
      • Schaefer E.J.
      Short-term consumption of a low-fat diet beneficially affects plasma lipid concentrations only when accompanied by weight loss. Hypercholesterolemia, low-fat diet, and plasma lipids.
      ). Likewise, it is difficult to accurately assess the effect of individual components of macronutrients on plasma lipoprotein patterns. For example, under isoweight conditions, if the intake of one fatty acid increases, another energy-containing component of the diet (fatty acid, amino acid, or saccharide) must decrease.
      The literature is replete with studies assessing many aspects of this topic. In is beyond the scope of the article to conduct a systematic review of the literature. The discussion will be limited to major current issues and examples provided for illustrative purposes only. Special considerations imposed by unique metabolic conditions will not be addressed.

      METHODOLOGICAL ISSUES

      There are a considerable number of methodological challenges associated with studies designed to assess the effect of diet composition on lipoprotein patterns. A cursory review of these issues provides some explanation for what often seems to be the appearance at best of contradictory and discordant data and at worst of a dearth of data on timely and critical topics.
      With respect to humans, there is a tremendous degree of genetic heterogeneity among individuals, the significance of which is likely to be considerable but difficult at this time to adequately quantify or manage. The amount of time humans can be subjected to strict diet control is limited, from the perspectives of cost, logistics, and subject cooperation, making it difficult to achieve a “steady state.” Metabolism varies by gender and age, and within each of these categories, multiple changes (e.g., hormonal and body composition) proceed at different rates, making them difficult to factor into the final analysis. Likewise, with aging come comorbidities, which make it difficult to initiate an intervention in a well-matched cohort. And finally, but of utmost importance, ethical and humanitarian considerations limit the types and extremes of interventions and the invasiveness of the techniques that can be used to characterize and monitor outcomes. Nonetheless, data that have been generated in humans, within clearly defined contexts, have provided some of the most valuable and longstanding knowledge in the area of diet and plasma lipoprotein patterns.
      With respect to nonhuman interventions, there is no ideal animal model, transgenic or knockout, or in vitro system that yields data consistently analogous to human data. This is attributable to inherent differences in such factors as the physiology of gastrointestinal tracts, the characteristics of endocrine and immune systems, the pathways and nature of lipoprotein metabolism, and differences in body composition and metabolic rates. Hence, although critical data have emerged from animal and in vitro systems, particularly with respect to questions that cannot be adequately addressed in humans, these data need to be treated as pieces of the puzzle, critical but considered with caution when out of context.

      DIETARY MACRONUTRIENTS

       Stable body weight

       Fat

      Early work focused on assessing the effect of the macronutrient content of the diet on plasma lipoprotein patterns, with specific emphasis on dietary fat and carbohydrate. It was noted early in the 1960s that diets very low in fat resulted in hypertriglyceridemia (
      • Ahrens Jr., E.H.
      • Hirsch J.
      • Oette K.
      • Farquhar J.W.
      • Stein Y.
      Carbohydrate-induced and fat-induced lipemia.
      ,
      • Lichtenstein A.H.
      • Van Horn L.
      Very low fat diets.
      ), and this effect was later attributed to increased rates of hepatic fatty acid synthesis (
      • Hudgins L.C.
      • Seidman C.E.
      • Diakun J.
      • Hirsch J.
      Human fatty acid synthesis is reduced after the substitution of dietary starch for sugar.
      ,
      • Raben A.
      • Holst J.J.
      • Madsen J.
      • Astrup A.
      Diurnal metabolic profiles after 14 d of an ad libitum high-starch, high-sucrose, or high-fat diet in normal-weight never-obese and postobese women.
      ) and the subsequent production of hepatic triglyceride-rich particles, such as VLDL (
      • Nestel P.J.
      • Hirsch E.Z.
      Triglyceride turnover after diets rich in carbohydrate or animal fat.
      ,
      • Nestel P.J.
      • Carroll K.F.
      • Havenstein N.
      Plasma triglyceride response to carbohydrates, fats and caloric intake.
      ). It was also observed that this hypertriglyceridemia was accompanied by lower HDL concentrations. Within the context of a stable body weight, replacement of dietary carbohydrate with fat resulted in lower triglyceride and VLDL cholesterol concentrations, higher HDL cholesterol concentrations, and a lower, more favorable total cholesterol-to-HDL cholesterol ratio (
      • Lichtenstein A.H.
      • Ausman L.M.
      • Carrasco W.
      • Jenner J.L.
      • Ordovas J.M.
      • Schaefer E.J.
      Short-term consumption of a low-fat diet beneficially affects plasma lipid concentrations only when accompanied by weight loss. Hypercholesterolemia, low-fat diet, and plasma lipids.
      ,
      • Grundy S.M.
      • Nix D.
      • Whelan M.F.
      • Franklin L.
      Comparison of three cholesterol-lowering diets in normolipidemic men.
      ,
      • Garg A.
      • Grundy S.M.
      • Koffler M.
      Effect of high carbohydrate intake on hyperglycemia, islet function, and plasma lipoproteins in NIDDM.
      ,
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ,
      • Mancini M.
      • Mattock M.
      • Rabaya E.
      • Chait A.
      • Lewis B.
      Studies of the mechanisms of carbohydrate-induced lipaemia in normal man.
      ). Additionally, the more moderate the shift in the fat-to-carbohydrate ratio of the diet, the more moderate the change in triglyceride concentrations (
      • Ginsberg H.N.
      • Kris-Etherton P.
      • Dennis B.
      • Elmer P.J.
      • Ershow A.
      • Lefevre M.
      • Pearson T.
      • Roheim P.
      • Ramakrishnan R.
      • Reed R.
      • et al.
      Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA study, protocol 1.
      ). Recently, it was reported that moderate carbohydrate restriction and weight loss provide equivalent but nonadditive improvements in the atherogenic dyslipidemic pattern characterized by increased triglyceride concentrations and total cholesterol-to-HDL cholesterol ratios (
      • Krauss R.M.
      • Blanche P.J.
      • Rawlings R.S.
      • Fernstrom H.S.
      • Williams P.T.
      Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia.
      ).

       Protein

      Until recently, there has been little work on the effect of dietary protein on plasma lipoprotein patterns. Target dietary recommendations as a percentage of energy have changed little over the years (
      • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
      ,
      • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).
      ,
      • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).
      ,
      • Anonymous
      Diet and coronary heart disease. A council statement.
      ,
      • Lichtenstein A.H.
      • Appel L.J.
      • Brands M.
      • Carnethon M.
      • Daniels S.
      • Franch H.A.
      • Franklin B.
      • Kris-Etherton P.
      • Harris W.S.
      • Howard B.
      • Karanja N.
      • Lefevre M.
      • Rudel L.
      • Sacks L.
      • Van Horn L.
      • Winston M.
      • Wylie-Rosett J.
      AHA diet and lifestyle recommendations revision 2006: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association.
      ). Dietary protein falls into two categories defined by origin: animal protein, primarily meat and diary; and vegetable protein, primarily grains and legumes. For the most part, the former source of protein contributes the majority of dietary saturated fat and much of the monounsaturated fat, whereas the latter, with the exception of tropical oils (palm, palm kernel, and coconut), contributes polyunsaturated and monounsaturated fat. The implications of fatty acids accompanying the sources of protein are discussed below. Although there has been considerable interest in recent years about the absolute level of protein on plasma lipoprotein patterns, it has not been possible to untangle the independent effect of the presence of protein from that of the absence of carbohydrate and/or a change in body weight. During the past decade, attention has been focused on the potential unique properties of one type of vegetable protein, soy protein, on plasma lipoprotein patterns (
      • Anderson J.W.
      • Johnstone B.M.
      • Cook-Newell M.E.
      Meta-analysis of the effects of soy protein intake on serum lipids.
      ). Recent work suggests that the initial beneficial effects on plasma lipoprotein concentrations relative to other types of protein, most commonly casein, have been more modest than originally thought (
      • Sacks F.M.
      • Lichtenstein A.
      • Van Horn L.
      • Harris W.
      • Kris-Etherton P.
      • Winston M.
      American Heart Association Nutrition Committee. Soy protein, isoflavones, and cardiovascular health: an American Heart Association science advisory for professionals from the Nutrition Committee.
      ,
      • Kreijkamp-Kaspers S.
      • Kok L.
      • Grobbee D.E.
      • de Haan E.H.
      • Aleman A.
      • Lampe J.W.
      • van der Schouw Y.T.
      Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial.
      ,
      • Lichtenstein A.H.
      • Jalbert S.M.
      • Adlercreutz H.
      • Goldin B.R.
      • Rasmussen H.
      • Schaefer E.J.
      • Ausman L.M.
      Lipoprotein response to diets high in soy or animal protein with and without isoflavones in moderately hypercholesterolemic subjects.
      ).

       Carbohydrate

      Because the majority of dietary interventions in humans have held the protein content of the diet relatively constant and varied the fat, by definition, under isoweight conditions, the carbohydrate component of the diet varied inversely with fat and protein. Hence, any observations made with respect to the fat content of the diet, as discussed above, likewise apply to dietary carbohydrate. Increases in the relative proportion of carbohydrate result in dyslipidemia, characterized by high triglyceride and VLDL cholesterol concentrations, low HDL cholesterol concentrations, high total cholesterol-to-HDL cholesterol ratios, and, in some cases, small dense LDL particles (
      • Lichtenstein A.H.
      • Ausman L.M.
      • Carrasco W.
      • Jenner J.L.
      • Ordovas J.M.
      • Schaefer E.J.
      Short-term consumption of a low-fat diet beneficially affects plasma lipid concentrations only when accompanied by weight loss. Hypercholesterolemia, low-fat diet, and plasma lipids.
      ,
      • Grundy S.M.
      • Nix D.
      • Whelan M.F.
      • Franklin L.
      Comparison of three cholesterol-lowering diets in normolipidemic men.
      ,
      • Garg A.
      • Grundy S.M.
      • Koffler M.
      Effect of high carbohydrate intake on hyperglycemia, islet function, and plasma lipoproteins in NIDDM.
      ,
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ,
      • Mancini M.
      • Mattock M.
      • Rabaya E.
      • Chait A.
      • Lewis B.
      Studies of the mechanisms of carbohydrate-induced lipaemia in normal man.
      ,
      • Li Z.
      • McNamara J.R.
      • Fruchart J.C.
      • Luc G.
      • Bard J.M.
      • Ordovas J.M.
      • Wilson P.W.
      • Schaefer E.J.
      Effects of gender and menopausal status on plasma lipoprotein subspecies and particle sizes.
      ,
      • Stampfer M.J.
      • Krauss R.M.
      • Ma J.
      • Blanche P.J.
      • Holl L.G.
      • Sacks F.M.
      • Hennekens C.H.
      A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.
      ). The extent of the response is dependent on the characteristics of the study population and the magnitude of the shift from fat to carbohydrate (
      • Kasim-Karakas S.E.
      • Almario R.U.
      • Mueller W.M.
      • Peerson J.
      Changes in plasma lipoproteins during low-fat, high-carbohydrate diets: effects of energy intake.
      ,
      • Lichtenstein A.H.
      • Ausman L.M.
      • Carrasco W.
      • Jenner J.L.
      • Ordovas J.M.
      • Schaefer E.J.
      Short-term consumption of a low-fat diet beneficially affects plasma lipid concentrations only when accompanied by weight loss. Hypercholesterolemia, low-fat diet, and plasma lipids.
      ,
      • Ginsberg H.N.
      • Kris-Etherton P.
      • Dennis B.
      • Elmer P.J.
      • Ershow A.
      • Lefevre M.
      • Pearson T.
      • Roheim P.
      • Ramakrishnan R.
      • Reed R.
      • et al.
      Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA study, protocol 1.
      ). There is limited information on type of carbohydrate (i.e., sucrose and starch) and plasma lipoprotein response. Diets high in starch, relative to sucrose, have been associated with lower total and LDL cholesterol and with fasting and nonfasting triglyceride concentrations in some but not all studies (
      • Raben A.
      • Holst J.J.
      • Madsen J.
      • Astrup A.
      Diurnal metabolic profiles after 14 d of an ad libitum high-starch, high-sucrose, or high-fat diet in normal-weight never-obese and postobese women.
      ,
      • Marckmann P.
      • Raben A.
      • Astrup A.
      Ad libitum intake of low-fat diets rich in either starchy foods or sucrose: effects on blood lipids, factor VII coagulant activity, and fibrinogen.
      ,
      • Surwit R.S.
      • Feinglos M.N.
      • McCaskill C.C.
      • Clay S.L.
      • Babyak M.A.
      • Brownlow B.S.
      • Plaisted C.S.
      • Lin P.H.
      Metabolic and behavioral effects of a high-sucrose diet during weight loss.
      ). However, the area under the curve for glucose and nonesterified fatty acids has been reported to be lower in response to diets high in sucrose relative to starch (
      • Raben A.
      • Holst J.J.
      • Madsen J.
      • Astrup A.
      Diurnal metabolic profiles after 14 d of an ad libitum high-starch, high-sucrose, or high-fat diet in normal-weight never-obese and postobese women.
      ). Confounding interpretation of these data, diets high in sugar relative to starch have been reported to increase rates of fatty acid synthesis (
      • Hudgins L.C.
      • Seidman C.E.
      • Diakun J.
      • Hirsch J.
      Human fatty acid synthesis is reduced after the substitution of dietary starch for sugar.
      ), perhaps reflecting differences in the rates of absorption, secondary to the presence of dietary fiber (
      • O'Dea K.
      • Traianedes K.
      • Ireland P.
      • Niall M.
      • Sadler J.
      • Hopper J.
      • De Luise M.
      The effects of diet differing in fat, carbohydrate, and fiber on carbohydrate and lipid metabolism in type II diabetes.
      ). Additional work in this area is needed.
      The issue of the effect of carbohydrate on the plasma lipoprotein response is further complicated by other unavoidable variables when using whole food diets, such as the type of saccharide (glucose, galactose, fructose) or the presence of fiber. In general, when the carbohydrate content of the diet declines, unless the decrease is limited to products made with highly refined foods, the fiber content of the diet also declines (
      • Salmeron J.
      • Ascherio A.
      • Rimm E.B.
      • Colditz G.A.
      • Spiegelman D.
      • Jenkins D.J.
      • Stampfer M.J.
      • Wing A.L.
      • Willett W.C.
      Dietary fiber, glycemic load, and risk of NIDDM in men.
      ,
      • Salmeron J.
      • Manson J.E.
      • Stampfer M.J.
      • Colditz G.A.
      • Wing A.L.
      • Willett W.C.
      Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women.
      ,
      • Hodge A.M.
      • English D.R.
      • O'Dea K.
      • Giles G.G.
      Glycemic index and dietary fiber and the risk of type 2 diabetes.
      ,
      • McKeown N.M.
      • Meigs J.B.
      • Liu S.
      • Saltzman E.
      • Wilson P.W.
      • Jacques P.F.
      Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort.
      ). Because dietary fiber has been shown to have a modest effect on reducing plasma total and LDL cholesterol concentrations (
      • Brown L.
      • Rosner B.
      • Willett W.W.
      • Sacks F.M.
      Cholesterol-lowering effects of dietary fiber: a meta-analysis.
      ,
      • Van Horn L.
      Fiber, lipids, and coronary heart disease. A statement for healthcare professionals from the Nutrition Committee, American Heart Association.
      ), the relative effect of a change in fiber compared with carbohydrate is difficult to attribute. The addition of fiber to equalize the amount in the diet can result in noncomparable types of fiber, further adding variability to the equation. The potential of other confounding bioactive dietary factors needs further investigation.

       Body weight change

      The recent interest in low-carbohydrate/high-protein diets has resulted in the generation of a considerable amount of longer term data on the effect of altering the macronutrient content of the diet within the context of weight loss and subsequent effects on plasma lipoprotein patterns. A recent meta-analysis (
      • Nordmann A.J.
      • Nordmann A.
      • Briel M.
      • Keller U.
      • Yancy Jr., W.S.
      • Brehm B.J.
      • Bucher H.C.
      Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials.
      ) of the six trials (
      • Brehm B.J.
      • Seeley R.J.
      • Daniels S.R.
      • D'Alessio D.A.
      A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women.
      ,
      • Foster G.D.
      • Wyatt H.R.
      • Hill J.O.
      • McGuckin B.G.
      • Brill C.
      • Mohammed B.S.
      • Szapary P.O.
      • Rader D.J.
      • Edman J.S.
      • Klein S.
      A randomized trial of a low-carbohydrate diet for obesity.
      ,
      • Samaha F.F.
      • Iqbal N.
      • Seshadri P.
      • Chicano K.L.
      • Daily D.A.
      • McGrory J.
      • Williams T.
      • Williams M.
      • Gracely E.J.
      • Stern L.
      A low-carbohydrate as compared with a low-fat diet in severe obesity.
      ,
      • Yancy Jr., W.S.
      • Olsen M.K.
      • Guyton J.R.
      • Bakst R.P.
      • Westman E.C.
      A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial.
      ,
      • Dansinger M.L.
      • Gleason J.A.
      • Griffith J.L.
      • Selker H.P.
      • Schaefer E.J.
      Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial.
      ,
      • Stern L.
      • Iqbal N.
      • Seshadri P.
      • Chicano K.L.
      • Daily D.A.
      • McGrory J.
      • Williams M.
      • Gracely E.J.
      • Samaha F.F.
      The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial.
      ) comparing low-carbohydrate/high-protein diets with low-fat diets for at least 6 months yielded the following results. As an aggregate, at the 6 month time point, the low-carbohydrate/high-protein diets resulted in more favorable effects on plasma triglycerides and HDL cholesterol concentrations, less favorable effects on plasma total and LDL cholesterol concentrations, and a greater decrease in body weight. In the one study in which the intervention relied on providing subjects with popular diet books and little individualized support, similar to what is frequently experienced by the general population, body weight loss and plasma lipoprotein responses were similar regardless of the recommended macronutrient content of the diet (
      • Dansinger M.L.
      • Gleason J.A.
      • Griffith J.L.
      • Selker H.P.
      • Schaefer E.J.
      Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial.
      ). In those studies for which data were available after 12 months (
      • Foster G.D.
      • Wyatt H.R.
      • Hill J.O.
      • McGuckin B.G.
      • Brill C.
      • Mohammed B.S.
      • Szapary P.O.
      • Rader D.J.
      • Edman J.S.
      • Klein S.
      A randomized trial of a low-carbohydrate diet for obesity.
      ,
      • Dansinger M.L.
      • Gleason J.A.
      • Griffith J.L.
      • Selker H.P.
      • Schaefer E.J.
      Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial.
      ,
      • Stern L.
      • Iqbal N.
      • Seshadri P.
      • Chicano K.L.
      • Daily D.A.
      • McGrory J.
      • Williams M.
      • Gracely E.J.
      • Samaha F.F.
      The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial.
      ), the more favorable effects of the low-carbohydrate/high-protein diets were maintained at a statistically significant level for plasma triglyceride but not for HDL cholesterol concentrations, whereas the less favorable effects on total and LDL cholesterol remained significant. Additionally, by the 12 month time point, the significant difference in body weights was not maintained.
      In contrast to weight loss studies in overweight and obese individuals, there are limited long-term data in underweight or lean subjects on the response of lipoprotein patterns to diets differing in macronutrient content that involve weight gain. One unique short-term study addressing this issue involved the Tarahumara Indians (
      • McMurry M.P.
      • Cerqueira M.T.
      • Connor S.L.
      • Connor W.E.
      Changes in lipid and lipoprotein levels and body weight in Tarahumara Indians after consumption of an affluent diet.
      ). Subjects were shifted from their traditional diet of 20 energy (E) % fat, 15 E% protein, and 65 E% carbohydrate to an “affluent diet” of 43 E% fat, 10 E% protein, and 47 E% carbohydrate, at approximately twice the energy level habitually consumed. Within the context of a short-term increase in body weight, plasma total cholesterol, LDL cholesterol, and HDL cholesterol concentrations increased, as did the calculated mean total cholesterol-to-HDL cholesterol ratio.

       Dietary fatty acids

      It has been recognized since the 1950s that the fatty acid profile of the diet is the major determinant of plasma cholesterol concentrations (
      • Hegsted D.M.
      • Gotsis A.
      • Stare F.J.
      • Worcester J.
      Interrelations between the kind and amount of dietary fat and dietary cholesterol in experimental hypercholesterolemia.
      ,
      • Keys A.
      • Mickelsen O.
      • Miller E.O.
      • Chapman C.B.
      The relation in man between cholesterol levels in the diet and in the blood.
      ). When displacing carbohydrate from the diet, saturated fatty acids increase total cholesterol, polyunsaturated fatty acids decrease total cholesterol, and monounsaturated fatty acids have a neutral effect (
      • Hegsted D.M.
      • Gotsis A.
      • Stare F.J.
      • Worcester J.
      Interrelations between the kind and amount of dietary fat and dietary cholesterol in experimental hypercholesterolemia.
      ,
      • Keys A.
      • Mickelsen O.
      • Miller E.O.
      • Chapman C.B.
      The relation in man between cholesterol levels in the diet and in the blood.
      ,
      • Clarke R.
      • Frost C.
      • Collins R.
      • Appleby P.
      • Peto R.
      Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.
      ). It is estimated that the total cholesterol-increasing effect of saturated fatty acids is approximately twice the cholesterol-decreasing effect of polyunsaturated fatty acids, resulting in early dietary recommendations that stressed reductions in dietary saturated fat (
      • Anonymous
      Diet and coronary heart disease. A council statement.
      ). More recent work has concluded that saturated fatty acids, particularly lauric (12:0), myristic (14:0), and palmitic (16:0) acids, increase LDL and HDL cholesterol, polyunsaturated fatty acids decrease LDL and HDL cholesterol, and monounsaturated fatty acids, to a lesser extent than polyunsaturated fatty acids, decrease LDL and HDL cholesterol concentrations (
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ,
      • Clarke R.
      • Frost C.
      • Collins R.
      • Appleby P.
      • Peto R.
      Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.
      ,
      • Yu S.
      • Derr J.
      • Etherton T.D.
      • Kris-Etherton P.M.
      Plasma cholesterol-predictive equations demonstrate that stearic acid is neutral and monounsaturated fatty acids are hypocholesterolemic.
      ). The total cholesterol-to-HDL cholesterol ratio is similar and more favorable for polyunsaturated and monounsaturated fatty acids than for saturated fatty acids (
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ). Similarly, observational data suggest polyunsaturated and monounsaturated fatty acid, relative to saturated fatty acids, intakes are associated with reduced CVD risk (
      • Hu F.B.
      • Stampfer M.J.
      • Manson J.E.
      • Rimm E.
      • Colditz G.A.
      • Rosner B.A.
      • Hennekens C.H.
      • Willett W.C.
      Dietary fat intake and the risk of coronary heart disease in women.
      ).

       Saturated fatty acids

      In the mid-1950s, it was also noted that not all saturated fatty acids had identical effects on plasma cholesterol concentrations. Shorter chain saturated fatty acids (6:0–10:0) and 18:0 have little effect on plasma cholesterol concentrations, whereas those with intermediate chain lengths (12:0–16:0) increase concentrations (
      • Keys A.
      • Anderson J.T.
      • Grande F.
      Serum cholesterol response to changes in the diet.
      ,
      • McGandy R.B.
      • Hegsted D.M.
      • Myers M.L.
      Use of semisynthetic fats in determining effects of specific dietary fatty acids on serum lipids in man.
      ). The minimal effect of the shorter chain fatty acids is attributed to their being absorbed directly into the portal circulation, and that of 18:0 is attributed to its high rate of conversion to 18:1, a monounsaturated fatty acid (
      • Bonanome A.
      • Grundy S.M.
      Effect of dietary stearic acid on plasma cholesterol and lipoprotein levels.
      ). The LDL cholesterol-increasing effect of the intermediate chain saturated fat is attributed to a decreased fractional catabolic rate of plasma LDL, with little effect on production rate (
      • Shepherd J.
      • Packard C.J.
      • Grundy S.M.
      • Yeshurun D.
      • Gotto Jr., A.M.
      • Taunton O.D.
      Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man.
      ,
      • Matthan N.R.
      • Welty F.K.
      • Barrett P.H.
      • Harausz C.
      • Dolnikowski G.G.
      • Parks J.S.
      • Eckel R.H.
      • Schaefer E.J.
      • Lichtenstein A.H.
      Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women.
      ). Predictive equations used to estimate the effect of alterations in the major dietary fatty acid subclasses, relative to carbohydrate, assume that the plasma cholesterol-increasing effect of saturated fat is approximately twice the cholesterol-decreasing effect of polyunsaturated fat. At this time, the predicative equations have factors for saturated, monounsaturated, and/or polyunsaturated fatty acids and do not take into consideration the differences among individual saturated fatty acids (
      • Yu S.
      • Derr J.
      • Etherton T.D.
      • Kris-Etherton P.M.
      Plasma cholesterol-predictive equations demonstrate that stearic acid is neutral and monounsaturated fatty acids are hypocholesterolemic.
      ,
      • Keys A.
      • Anderson J.T.
      • Grande F.
      Serum cholesterol response to changes in the diet.
      ,
      • Hegsted D.M.
      Serum-cholesterol response to dietary cholesterol: a re-evaluation.
      ,
      • Mensink R.P.
      • Katan M.B.
      Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials.
      ). Given that each food contains a mixture of fatty acids and the difficulty in accurately assessing the fatty acid profile of the diet, this approach is reasonable at this time. Likewise, from a dietary perspective, it is difficult to formulate recommendations on the basis of the differential effects among saturated fatty acids and CVD risk. Hence, the focus has been to recommend restrictions of total saturated fat intake (
      • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).
      ,
      • Lichtenstein A.H.
      • Appel L.J.
      • Brands M.
      • Carnethon M.
      • Daniels S.
      • Franch H.A.
      • Franklin B.
      • Kris-Etherton P.
      • Harris W.S.
      • Howard B.
      • Karanja N.
      • Lefevre M.
      • Rudel L.
      • Sacks L.
      • Van Horn L.
      • Winston M.
      • Wylie-Rosett J.
      AHA diet and lifestyle recommendations revision 2006: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association.
      ). With the rapid development of the technology for genetic modification of the fatty acid profiles of plants and animals, this approach may need to be revisited as these foods become commercially available on a large scale (
      • Lai L.
      • Kang J.X.
      • Li R.
      • Wang J.
      • Wilt W.T.
      • Yong H.Y.
      • Hao Y.
      • Wax D.M.
      • Murphy C.N.
      • Rieke A.
      • Samuel M.
      • Linville M.L.
      • Corte S.W.
      • Evans R.W.
      • Starzi T.E.
      • Prather P.S.
      • Dai Y.
      Generation of cloned transgenic pigs rich in omega-3 fatty acids.
      ,
      • Hazebroek J.P.
      Analysis of genetically modified oils.
      ,
      • Broun P.
      • Gettner S.
      • Somerville C.
      Genetic engineering of plant lipids.
      ,
      • Broun P.
      • Somerville C.
      Progress in plant metabolic engineering.
      ).

       Unsaturated fatty acids

      Dietary unsaturated fatty acids are categorized by the length of their acyl chains, the degree of unsaturation (number of double bonds), the position of the double bond(s), and the conformation of the double bond(s). From the perspective of diet and CVD risk, all of these factors are important in dictating the biological effects of the individual unsaturated fatty acids on plasma lipoprotein patterns. With respect to chain length, the major dietary unsaturated fatty acids range from 18 to 22 carbons, with shorter and longer chain unsaturated fatty acids occurring in relatively small amounts. Although there are multiple nomenclatures for denoting the position of the double bonds for categorical purposes, the distinction from a biological perspective is made on the basis of the location of the first double bond from the methyl end of the fatty acyl chain (as opposed to the carboxyl end). Two major dietary subclasses of polyunsaturated fatty acids are ω-6 (or n-6) and ω-3 (or n-3). These fatty acids can have an identical chemical composition but differ in the location of double bonds. They are referred to as positional isomers. In addition, the double bonds can occur in either the cis or trans configuration. Trans double bonds have a greater bond angle than cis double bonds; resulting in acyl chains with a more linear conformation, similar to a saturated than an unsaturated fatty acid. Fatty acids with an identical composition but double bonds differing in conformation are referred to as geometric isomers.

       ω-3 fatty acids

      Interest in the protective effect of very long-chain ω-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on CVD began in earnest in the 1970s (
      • Dyerberg J.
      • Bang H.O.
      • Hjorne N.
      Fatty acid composition of the plasma lipids in Greenland Eskimos.
      ,
      • Bang H.O.
      • Dyerberg J.
      • Nielsen A.B.
      Plasma lipid and lipoprotein pattern in Greenlandic west-coast Eskimos.
      ). These observations have been supported by a considerable number of observational studies (
      • Albert C.M.
      • Campos H.
      • Stampfer M.J.
      • Ridker P.M.
      • Manson J.E.
      • Willett W.C.
      • Ma J.
      Blood levels of long-chain n-3 fatty acids and the risk of sudden death.
      ,
      • Albert C.M.
      • Hennekens C.H.
      • O'Donnell C.J.
      • Ajani U.A.
      • Carey V.J.
      • Willett W.C.
      • Ruskin J.N.
      • Manson J.E.
      Fish consumption and risk of sudden cardiac death.
      ,
      • Erkkila A.T.
      • Lichtenstein A.H.
      • Mozaffarian D.
      • Herrington D.M.
      Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease.
      ,
      • Mozaffarian D.
      • Gottdiener J.S.
      • Siscovick D.S.
      Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics.
      ,
      • Siscovick D.S.
      • Raghunathan T.E.
      • King I.
      • Weinmann S.
      • Wicklund K.G.
      • Albright J.
      • Bovbjerg V.
      • Arbogast P.
      • Smith H.
      • Kushi L.H.
      • et al.
      Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest.
      ) and some interventional studies (
      • GISSI
      Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
      ,
      • Kris-Etherton P.M.
      • Harris W.S.
      • Appel L.J.
      Nutrition Committee
      Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
      ). Recently, there have been a number of systematic reviews and meta-analyses of the relationship of dietary ω-3 fatty acids and CVD events. The majority of them concluded that the inverse relationship between ω-3 fatty acid intake and CVD events is significant for EPA and DHA but not for α-linolenic acid (ALA) (
      • Wang C.
      • Chung M.
      • Balk E.
      • Kupelnick B.
      • Jordan H.
      • Harris W.
      • Lichtenstein A.
      • Lau J.
      N-3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.
      ,
      • Balk E.M.
      • Lichtenstein A.H.
      • Chung M.
      • Kupelnick B.
      • Chew P.
      • Lau J.
      Effects of omega-3 fatty acids on coronary restenosis, intima-media thickness, and exercise tolerance: a systematic review.
      ,
      • Hooper L.
      • Thompson R.L.
      • Harrison R.A.
      • Summerbell C.D.
      • Ness A.R.
      • Moore H.J.
      • Worthington H.V.
      • Durrington P.N.
      • Higgins J.P.
      • Capps N.E.
      • et al.
      Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.
      ,
      • Bouzan C.
      • Cohen J.T.
      • Connor W.E.
      • Kris-Etherton P.M.
      • Gray G.M.
      • Konig A.
      • Lawrence R.S.
      • Savitz D.A.
      • Teutsch S.M.
      A quantitative analysis of fish consumption and stroke risk.
      ,
      • Konig A.
      • Bouzan C.
      • Cohen J.T.
      • Connor W.E.
      • Kris-Etherton P.M.
      • Gray G.M.
      • Lawrence R.S.
      • Savitz D.A.
      • Teutsch S.M.
      A quantitative analysis of fish consumption and coronary heart disease mortality.
      ).
      The major dietary source of EPA and DHA is oily fish. A plant source of ω-3 fatty acids, ALA, can be converted to EPA, albeit at very low rates (∼5%) (
      • Brenna J.T.
      Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man.
      ). Major dietary sources of ALA are canola and soybean oils. It has been suggested that the inefficient conversion of ALA to EPA can be attributed to the limited incorporation of ALA into the hepatic phospholipid pool (
      • Goyens P.L.
      • Spilker M.E.
      • Zock P.L.
      • Katan M.B.
      • Mensink R.P.
      Compartmental modeling to quantify alpha-linolenic acid conversion after longer term intake of multiple tracer boluses.
      ). It has likewise been suggested that the inefficient conversion of EPA to DHA can be attributed to the low rate of conversion of EPA into docosapentaenoic acid, which is necessary for the subsequent conversion to DHA (
      • Goyens P.L.
      • Spilker M.E.
      • Zock P.L.
      • Katan M.B.
      • Mensink R.P.
      Compartmental modeling to quantify alpha-linolenic acid conversion after longer term intake of multiple tracer boluses.
      ).
      It is likely that the purported beneficial effects of the very long-chain fatty acids on CVD risk are multifactorial (
      • Matthan N.R.
      • Jordan H.
      • Chung M.
      • Lichtenstein A.H.
      • Lathrop D.A.
      • Lau J.
      A systematic review and meta-analysis of the impact of omega-3 fatty acids on selected arrhythmia outcomes in animal models.
      ). The postulated mechanisms underlying the relationship include decreased arrhythmias, lower triglyceride concentrations in hypertrigyceridemic individuals, lower blood pressure, and decreased platelet aggregation (
      • Kris-Etherton P.M.
      • Harris W.S.
      • Appel L.J.
      Nutrition Committee
      Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
      ,
      • Nair S.S.
      • Leitch J.W.
      • Falconer J.
      • Garg M.L.
      Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action.
      ,
      • Appel L.J.
      • Miller 3rd, E.R.
      • Seidler A.J.
      • Whelton P.K.
      Does supplementation of diet with “fish oil” reduce blood pressure? A meta-analysis of controlled clinical trials.
      ). In individuals with increased triglyceride levels, ω-3 fatty acids decrease plasma concentrations by decreasing hepatic production rates of VLDL, with little effect on fractional catabolic rates (
      • Chan D.C.
      • Watts G.F.
      • Mori T.A.
      • Barrett P.H.
      • Redgrave T.G.
      • Beilin L.J.
      Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity.
      ,
      • Nestel P.J.
      • Connor W.E.
      • Reardon M.F.
      • Connor S.
      • Wong S.
      • Boston R.
      Suppression by diets rich in fish oil of very low density lipoprotein production in man.
      ). In some cases, an increase in LDL cholesterol concentration has been attributed to very long-chain ω-3 fatty acids, in part as a result of an increased conversion rate of VLDL to LDL (
      • Chan D.C.
      • Watts G.F.
      • Mori T.A.
      • Barrett P.H.
      • Redgrave T.G.
      • Beilin L.J.
      Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity.
      ,
      • Huff M.W.
      • Telford D.E.
      Dietary fish oil increases conversion of very low density lipoprotein apoprotein B to low density lipoprotein.
      ). ω-3 fatty acids decrease postprandial plasma triglyceride concentrations by accelerating the fractional catabolic rate via increased lipoprotein lipase activity (
      • Park Y.
      • Harris W.S.
      Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance.
      ). On the basis of the available data, the American Heart Association recommends that the general population consume at least two fish meals per week, individuals with established CVD consume 1 g of EPA plus DHA per day, and hypertriglyceridemic individuals consume 2–4 g of EPA plus DHA per day (
      • Kris-Etherton P.M.
      • Harris W.S.
      • Appel L.J.
      Nutrition Committee
      Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
      ).

       Trans fatty acids

      Trans fatty acids, by definition, contain at least one double bond in the trans configuration and can be either monounsaturated or polyunsaturated. Since the early 1990s, considerable attention has been focused on the effect of trans fatty acids on plasma lipid and lipoprotein concentrations (
      • Mensink R.P.
      • Katan M.B.
      Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects.
      ). The major source of dietary trans fatty acids is partially hydrogenated fats and products formulated with these fats, such as commercially prepared baked and fried foods. A smaller proportion of dietary trans fatty acids comes from ruminant animal fats found primarily in meat and full fat dairy products. As do saturated fatty acids, trans fatty acids increase LDL cholesterol concentrations (
      • Mensink R.P.
      • Katan M.B.
      Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects.
      ,
      • Lichtenstein A.H.
      • Ausman L.A.
      • Jalbert S.M.
      • Schaefer E.J.
      Comparison of different forms of hydrogenated fats on serum lipid levels in moderately hypercholesterolemic female and male subjects.
      ,
      • Judd J.T.
      • Clevidence B.A.
      • Muesing R.A.
      • Wittes J.
      • Sunkin M.E.
      • Podczasy J.J.
      Dietary trans fatty acids: effects on plasma lipids and lipoproteins of healthy men and women.
      ). In contrast to saturated fatty acids, they do not increase HDL cholesterol concentrations. Relative to unsaturated fat, both saturated fat and partially hydrogenated fat result in higher LDL cholesterol concentrations attributable to lower fractional catabolic rates, with little change in production rates (
      • Matthan N.R.
      • Welty F.K.
      • Barrett P.H.
      • Harausz C.
      • Dolnikowski G.G.
      • Parks J.S.
      • Eckel R.H.
      • Schaefer E.J.
      • Lichtenstein A.H.
      Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women.
      ). Relative to saturated fat, partially hydrogenated fat results in lower HDL cholesterol concentrations attributable to higher fractional catabolic rates, with little change in production rates (
      • Matthan N.R.
      • Welty F.K.
      • Barrett P.H.
      • Harausz C.
      • Dolnikowski G.G.
      • Parks J.S.
      • Eckel R.H.
      • Schaefer E.J.
      • Lichtenstein A.H.
      Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women.
      ). Collectively, these changes result in a less favorable total cholesterol or LDL cholesterol-to-HDL cholesterol ratio when trans fat is compared with saturated fat (
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ,
      • Ascherio A.
      • Katan M.B.
      • Zock P.L.
      • Stampfer M.J.
      • Willett W.C.
      Trans fatty acids and coronary heart disease.
      ,
      • Mozaffarian D.
      • Katan M.B.
      • Ascherio A.
      • Stampfer M.J.
      • Willett W.C.
      Trans fatty acids and cardiovascular disease.
      ). In some cases, trans fatty acids have also been reported to increase triglyceride concentrations (
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ,
      • Lichtenstein A.H.
      • Ausman L.A.
      • Jalbert S.M.
      • Schaefer E.J.
      Comparison of different forms of hydrogenated fats on serum lipid levels in moderately hypercholesterolemic female and male subjects.
      ).

       Dietary cholesterol

      The link between dietary cholesterol and increased plasma cholesterol concentrations and atherogenesis was originally made in the early 20th century in rabbits (
      • Finking G.
      • Hanke H.
      Nikolaj Nikolajewitsch Anitschkow (1885–1964) established the cholesterol-fed rabbit as a model for atherosclerosis research.
      ). Although the major determinant of LDL cholesterol concentrations in humans is saturated fat (
      • Keys A.
      • Anderson J.T.
      • Grande F.
      Serum cholesterol response to changes in the diet.
      ,
      • Hegsted D.M.
      Serum-cholesterol response to dietary cholesterol: a re-evaluation.
      ), dietary cholesterol has nonetheless been positively associated with CVD risk and both LDL and HDL cholesterol concentrations (
      • Clarke R.
      • Frost C.
      • Collins R.
      • Appleby P.
      • Peto R.
      Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.
      ,
      • Stamler J.
      • Shekelle R.
      Dietary cholesterol and human coronary heart disease. The epidemiologic evidence.
      ). Estimating the absolute effect of dietary cholesterol on plasma lipoprotein concentrations has been difficult because of the high degree of variability in response among individuals (
      • Katan M.B.
      • Beynen A.C.
      Characteristics of human hypo- and hyperresponders to dietary cholesterol.
      ). Nonetheless, in carefully controlled studies performed in healthy young males and females, it was demonstrated that for every additional 100 mg of dietary cholesterol, fasting plasma total cholesterol concentrations increased by 1.47 and 0.73 mg/dl, respectively, with parallel increases in LDL cholesterol and apoprotein B concentrations (
      • Ginsberg H.N.
      • Karmally W.
      • Siddiqui M.
      • Holleran S.
      • Tall A.R.
      • Blaner W.S.
      • Ramakrishnan R.
      Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women.
      ,
      • Ginsberg H.N.
      • Karmally W.
      • Siddiqui M.
      • Holleran S.
      • Tall A.R.
      • Rumsey S.C.
      • Deckelbaum R.J.
      • Blaner W.S.
      • Ramakrishnan R.
      A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men.
      ). Increased levels of the cholesteryl ester transfer protein were observed at the highest levels of dietary cholesterol in males but not females. One mechanism by which dietary cholesterol alters plasma lipoprotein concentrations is by downregulating cell surface LDL receptor activity, thereby decreasing VLDL and LDL clearance from plasma and increasing the conversion rate of VLDL to LDL (
      • Grundy S.M.
      • Denke M.A.
      Dietary influences on serum lipids and lipoproteins.
      ). Consistent with these data, dietary cholesterol has been reported to decrease LDL fractional catabolic rates and increase LDL production rates (
      • Packard C.J.
      • McKinney L.
      • Carr K.
      • Shepherd J.
      Cholesterol feeding increases low density lipoprotein synthesis.
      ). The identification of genetic polymorphisms that alter rates of cholesterol absorption is likely to shed new light in this area (
      • Ye S.Q.
      • Kwiterovich Jr., P.O.
      Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol.
      ,
      • Clifton P.
      • Kind K.
      • Jones C.
      • Noakes M.
      Response to dietary fat and cholesterol and genetic polymorphisms.
      ,
      • Cohen J.C.
      • Pertsemlidis A.
      • Fahmi S.
      • Esmail S.
      • Vega G.L.
      • Grundy S.M.
      • Hobbs H.H.
      Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.
      ).

      CONCLUSIONS

      It is difficult to isolate the independent effects of dietary fat, carbohydrate, and protein on plasma lipoprotein profiles. The data available are confounded by changes in body weight and alterations in the intake of two or more macronutrients necessitated to minimize body weight changes. Given the high degree of variability in response among individuals, specific recommendations for dietary fat, carbohydrate, and protein to optimize plasma lipoprotein patterns need to be made on a case-by-case basis, taking into consideration a realistic anticipated level of compliance. A considerable amount is known about the effect of fatty acid subclasses, and in some cases individual fatty acids, on plasma lipoprotein patterns and the metabolic basis for these effects. Additional efforts need to be focused on gaining a better understanding of the effect of the macronutrient content of the diet on established and emerging CVD risk factors other than lipoprotein patterns, understanding the mechanisms associated with diet induced changes in lipoprotein patterns and contributors to individual variability in response, and then to reassess and if necessary modify current recommendations.

      Acknowledgments

      This work was supported in part by National Institutes of Health Grant HL-54727 and the U.S. Department of Agriculture, under agreement 58-1950-4-401.

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