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Bempedoic acid has emerged as a potent inhibitor of ATP-citrate lyase (ACLY), a target for the reduction of LDL cholesterol (LDL-C). We review the impact of bempedoic acid treatment on lipoprotein metabolism and atherosclerosis in preclinical models and patients with hypercholesterolemia.The liver-specific activation of bempedoic acid inhibits ACLY, a key enzyme linking glucose catabolism to lipogenesis by catalyzing the formation of acetyl-CoA from mitochondrial-derived citrate for de novo synthesis of fatty acids and cholesterol. Adenosine monophosphate-activated protein kinase activation by bempedoic acid is not required for its lipid-regulating effects in vivo. Mendelian randomization of large human study cohorts has validated ACLY inhibition as a target for LDL-C lowering and atheroprotection. In rodents, bempedoic acid decreases plasma cholesterol and triglycerides, and prevents hepatic steatosis. In apolipoprotein E-deficient (Apoe) mice, LDL receptor-deficient (Ldlr) mice and LDLR-deficient miniature pigs, bempedoic acid reduces LDL-C and attenuates atherosclerosis. LDLR expression and activity are increased in primary human hepatocytes and in Apoe mouse liver treated with bempedoic acid suggesting a mechanism for LDL-C lowering, although additional pathways are likely involved. Phase 2 and 3 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients. Treatment does not affect plasma concentrations of triglyceride or other lipoproteins.The LDL-C-lowering and attenuated atherosclerosis in animal models and reduced LDL-C in hypercholesterolemic patients has validated ACLY inhibition as a therapeutic strategy. Positive results from phase 3 long-term cardiovascular outcome trials in high-risk patients are required for bempedoic acid to be approved for prevention of atherosclerosis.

Purpose of review The intestine is highly efficient at absorbing and packaging dietary lipids onto the structural protein apoB48 for distribution throughout the body. Here, we summarize recent advances into understanding the physiological and pharmacological actions of the proglucagon-derived peptides: glucagon like peptide 1 (GLP-1) and glucagon like peptide 2 (GLP-2) on intestinal lipoprotein secretion. Recent findings Several recent studies have elucidated mechanisms underlying the paradoxical effects of GLP-1 and GLP-2 on intestinal production of triglyceride-rich lipoproteins (TRLs). Both gut-derived peptides are secreted on an equimolar basis in response to the same nutrient stimulus. Despite neither receptor demonstrating clear localization to enterocytes, a single injection of a GLP-1R agonist rapidly decreases delivery of intestinally packaged fatty acids into the plasma, while conversely GLP-2 receptor (GLP-2R) activation acutely increases TRL concentrations in plasma. Summary The regulation of TRL secretion is dependent on the coordination of many processes: fatty acid availability uptake, assembly onto the apoB48 polypeptide backbone, secretion and reuptake, which the hormonal, neural, inflammatory and metabolic milieu can all strongly influence. Understanding of how GLP-1 and GLP-2 receptor agonists control TRL production has clinical importance given that GLP1R agonists were recently demonstrated not only to provide glycemic control but also to prevent major adverse cardiovascular events in patients with T2DM and the success of GLP-2R agonists in treating short bowel disease.

Apolipoprotein (apo) C-III is a key player in triglyceride-rich lipoprotein metabolism and strongly associated with elevated plasma triglyceride levels. Several new studies added important insights on apoC-III and its physiological function confirming its promise as a valid therapeutic target.APOC3 is expressed in liver and intestine and regulates triglyceride-rich lipoprotein (TRL) catabolism and anabolism. The transcriptional regulation in both organs requires different regulatory elements. Clinical and preclinical studies established that apoC-III raises plasma triglyceride levels predominantly by inhibiting hepatic TRL clearance. Mechanistic insights into missense variants indicate accelerated renal clearance of apoC-III variants resulting in enhanced TRL catabolism. In contrast, an APOC3 gain-of-function variant enhances de novo lipogenesis and hepatic TRL production. Multiple studies confirmed the correlation between increased apoC-III levels and cardiovascular disease. This has opened up new therapeutic avenues allowing targeting of specific apoC-III properties in triglyceride metabolism.Novel in vivo models and APOC3 missense variants revealed unique mechanisms by which apoC-III inhibits TRL catabolism. Clinical trials with Volanesorsen, an APOC3 antisense oligonucleotide, report very promising lipid-lowering outcomes. However, future studies will need to address if acute apoC-III lowering will have the same clinical benefits as a life-long reduction.

Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism.Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects.Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear.

Few studies have reviewed the impact of dietary fat and dietary patterns on lipoprotein metabolism. This review intends to provide perspective on this topic, while focusing primarily on the studies that assessed intravascular lipoprotein kinetics in humans using isotope methodologies.Data suggest that dietary saturated fatty acids slow the clearance of LDL apolipoprotein (apo)B-100 and of apoA-I from the circulation, whereas possibly increasing also apoA-I production. Dietary trans fats reduce the clearance of LDL apoB-100, whereas increasing the clearance of apoA-I. n-3 polyunsaturated fatty acids (PUFAs) intake reduces the production of apoB-48-containing lipoproteins as well as of VLDL apoB-100 and increases their conversion into smaller lipoproteins. Medium-chain triglycerides appear to have no significant effect on lipoprotein kinetics. Finally, Mediterranean diet in the absence of weight loss reduces LDL cholesterol, primarily by enhancing its clearance from the circulation.Kinetic studies with tracers allow a better appreciation of the impact of specific dietary factors on plasma lipid risk factors. However, additional studies are required to better document the effect of monounsaturated fatty acids, n-6 PUFAs, and of whole diets on lipoprotein metabolism.

Purpose of review Several lines of evidence indicate that the enterocyte plays a pivotal role in cholesterol homeostasis. The development of the selective inhibitor of cholesterol absorption ezetimibe and bile acid sequestrants (BAS) interrupting the enterohepatic circulation of bile salts has expanded the options for preventing and treating cardiovascular disease. We discuss here a selection of recently published studies that evaluated the effects of ezetimibe and BAS on lipoprotein metabolism. Recent findings Although significant progress has been made in recent years in elucidating the impacts of ezetimibe and BAS on lipoprotein metabolism, underlying mechanisms are not completely understood. Important new insights have been provided by using in-vivo kinetic studies of apolipoproteins labelled with a stable isotope. Other reports indicated that ezetimibe and BAS modulate the expression of several key genes involved in intestinal lipoprotein metabolism. Many of these effects have been related to the local effects of ezetimibe and BAS on intestinal cholesterol homeostasis. Summary A substantial effort is being made by researchers to fully understand the mechanisms by which ezetimibe and BAS improve lipid profile. The efficacy of combination therapy of statins with ezetimibe or BAS for the prevention of cardiovascular disease remains to be confirmed in clinical endpoint studies.

MicroRNAs (miRNAs) regulate gene expression by binding to target mRNAs and control a wide range of biological functions. Recent reports have identified specific miRNAs as major regulators of fatty acid and cholesterol homeostasis. This review examines the biological function of various miRNAs and the emerging evidence linking specific miRNAs to critical pathways in lipid metabolism.Disruption of lipid balance can lead to metabolic disturbances and thus tight regulation is required to maintain lipid homeostasis. Recent studies have shown key roles for miR-33 and miR-122 in regulation of lipid metabolism, and further evidence implicates miR-370 in regulation of miR-122. In addition, miRNAs involved in adipogenesis (miR-378/378* and miR-27) as well as newly discovered miRNAs such as miR-613, miR-302a, and miR-168 have now been implicated in regulation of lipid metabolism.Growing evidence support key roles for miRNAs in regulating both cholesterol and fatty acid metabolism, leading to considerable interest in miRNAs as potential drug targets to modulate lipid and lipoprotein metabolism. MiRNA-based therapeutics hold considerable promise in the fight to curtail the growing epidemic of obesity and type 2 diabetes and the associated risk of atherosclerosis.

Purpose of reviewBone marrow transplantation (BMT) technology is a firmly established tool for studying atherosclerosis. Only recently it is helping us to understand the inflammatory mechanisms leading to the development of obesity, insulin resistance and type 2 diabetes. Here we review the use of BMT as a tool for studying the metabolic syndrome.Recent findingsBone marrow-derived cells, and particularly monocytes and macrophages, have been a major subject in the study of atherogenesis, and they are highly amenable for research purposes because of their application in bone marrow transplantations. For example, the many pathways studied using BMT have helped unmask ABC transporters as the genes controlling reverse cholesterol transport and foam cell formation, as well as other genes like CCR2 and I kappa B alpha controlling leukocyte development, migration and activation. The invasion of leukocytes, not only in the vessel wall, but also in adipose tissue and liver, shares many common mechanisms relevant to atherosclerosis and metabolic diseases.SummaryBMT is an efficient and versatile tool for assessing the roles of specific genes that are restricted to hematopoietic cells, and especially the monocytes and macrophages in metabolic syndrome and its related pathologies.

PURPOSE OF REVIEW: Bone marrow transplantation (BMT) technology is a firmly established tool for studying atherosclerosis. Only recently it is helping us to understand the inflammatory mechanisms leading to the development of obesity, insulin resistance and type 2 diabetes. Here we review the use of BMT as a tool for studying the metabolic syndrome. RECENT FINDINGS: Bone marrow-derived cells, and particularly monocytes and macrophages, have been a major subject in the study of atherogenesis, and they are highly amenable for research purposes because of their application in bone marrow transplantations. For example, the many pathways studied using BMT have helped unmask ABC transporters as the genes controlling reverse cholesterol transport and foam cell formation, as well as other genes like CCR2 and IkappaBalpha controlling leukocyte development, migration and activation. The invasion of leukocytes, not only in the vessel wall, but also in adipose tissue and liver, shares many common mechanisms relevant to atherosclerosis and metabolic diseases. SUMMARY: BMT is an efficient and versatile tool for assessing the roles of specific genes that are restricted to hematopoietic cells, and especially the monocytes and macrophages in metabolic syndrome and its related pathologies.

Recent genome-wide association studies (GWAS) have identified approximately 100 genomic loci that are associated with plasma lipid traits, two-thirds of which had never been previously associated with lipoprotein metabolism. Identification of the causal genes and variants, functional validation of these genes and biological pathways, and elucidation of molecular mechanisms is required and poses a daunting task.Human genetics have been used to recently 'validate' genes, such as LIPG, SCARB1 and ANGPTL3, which were previously implicated in lipoprotein metabolism through classical wet bench approaches. Additionally, many novel genes have been identified as associated with plasma lipid traits by GWAS, though only relatively few have been functionally validated through targeted sequencing and genetic manipulation in cells and animals. These types of studies have defined new roles in lipid metabolism for the novel lipid genes SORT1 and TRIB1. These examples demonstrate the ways in which human genetics can validate candidate genes, as well as provide a novel discovery that requires functional validation at the bench, and point towards a more complete understanding of the molecular physiology of lipoprotein metabolism.This review summarizes recent developments in the use of human genetics to validate candidate genes in lipoprotein metabolism as well as in the functional validation of novel GWAS loci associated with plasma lipid traits.

We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease risk. Special emphasis was placed on the evidence emerging from the association between genetic variability at the apolipoprotein A5 locus, lipid phenotypes and disease outcomes. Moreover, we address recent reports evaluating apolipoprotein A5 gene-environment interactions in relation to cardiovascular disease and its common risk factors.Several genetic association studies have continued to strengthen the position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors and pharmacological therapies. Moreover, genetic variants at this locus have been significantly associated with both coronary disease and stroke risks.Apolipoprotein A-V has an important role in lipid metabolism, specifically for triglyceride-rich lipoproteins. However, its mechanism of action is still poorly understood. Clinical significance at present comes largely from genetic studies showing a consistent association with plasma triglyceride concentrations. Moreover, the effects of common genetic variants on triglyceride concentrations and disease risk are further modulated by other factors such as diet, pharmacological interventions and BMI. Therefore, these genetic variants could be potentially used to predict cardiovascular disease risk and individualize therapeutic options to decrease cardiovascular disease risk.

Purpose of review We will discuss the diverse roles of lipoprotein receptors that contribute to the maintenance and integrity of the vascular wall. Recent findings Lipoprotein receptors function not only as transporters for cholesterol and other lipids. They also act as sensors and signal transducers through which the endothelium, macrophages and smooth muscle cells communicate with their environment. Summary Traditionally, lipoprotein receptors were thought of merely as transporters of cholesterol and triglycerides to specific target cells, either for the purpose of delivery and redistribution of nutrients, or for the destruction or clearance of modified (oxidized) lipids by macrophages. Only recently have we begun to appreciate that the same receptors engage in a much more sophisticated and multi-faceted interaction with their environment. Inasmuch, they not only act as mere transporters, but as surprisingly versatile and adaptive signal transducers and modulators throughout the vessel wall. These recent findings now begin to reshape our thinking of how such structurally different and evolutionarily unrelated lipoprotein receptors orchestrate the response of the vessel wall to mechanical or metabolic damage.

Nutritional interventions may favourably regulate dyslipoproteinemia and, hence, decrease cardiovascular disease risk. Lipoprotein kinetic studies afford a powerful approach to understanding and defining the mechanisms by which such interventions modulate lipoprotein metabolism. Stable isotope tracers and compartment models are now commonly employed for such studies. We review the recent application of tracer methodologies to the study of dyslipoproteinemia in the metabolic syndrome. We also focus on the effects of nutritional intervention studies that have addressed the effects of weight loss, n-3 fatty acids, plant sterols and alcohol on very low density lipoprotein, LDL and HDL metabolism. The potential for statin treatment as an adjunct to dietary modification is also discussed. New tracer methodologies are discussed, specifically those referring to reverse cholesterol transport. The nutritional interventions discussed in this review are readily transferable into clinical preventive practice. The potential benefits to be gained by weight loss and fish oil supplementation in the metabolic syndrome extend beyond their specific and positive effects on lipoprotein metabolism. Furthermore, recent developments in tracer methodologies afford new tools for probing the in-vivo pathways of lipoprotein metabolism in future studies.

Purpose of review Genome-wide association studies have been used as an unbiased tool to identify novel genes that contribute to variations in LDL cholesterol levels in the hopes of uncovering new biology and new therapeutic targets for the treatment of atherosclerotic cardiovascular disease. The locus identified by genome-wide association studies with the strongest association with LDL cholesterol and atherosclerotic cardiovascular disease is the 1p13 sortilin-1 (SORT1) locus. Here, we review the identification and characterization of this locus, the initial physiological studies describing the role of SORT1 in lipoprotein metabolism, and recent work that has begun to sort out the complexity of this role. Recent findings Studies by several groups support an important role for sortilin in lipoprotein metabolism; however, the directionality of the effect of sortilin on plasma cholesterol and its role in the secretion of hepatic lipoproteins remains controversial. Studies by several groups support a role for sortilin in inhibiting lipoprotein export, whereas other studies suggest that sortilin facilitates lipoprotein export. Summary Understanding the mechanism by which sortilin affects LDL cholesterol will increase our understanding of the regulation of lipoprotein metabolism and hepatic lipoprotein export and may also allow us to harness the power of the 1p13 SORT1 locus for the treatment of atherosclerotic cardiovascular disease.

Based on an improved molecular understanding of how bile acid metabolism is regulated, an exciting period of research developments can be expected. By new ways of stimulating cholesterol breakdown to bile acids, novel therapeutic principles can be forseen which will further improve our potential for treating and preventing atherosclerosis.

Familial combined hyperlipidaemia is the most common inherited hyperlipidaemia and is found in up to 10% of patients with premature myocardial infarction. The genetic and metabolic bases of the disorder have not yet been defined. This review discusses the important advances in the past year in our understanding of the different metabolic pathways contributing to the pathogenesis of familial combined hyperlipidaemia. Curr Opin Lipidol 9:189–196. © 1998 Lippincott–Raven Publishers

The receptor-mediated transfer of lipids between cells and lipoproteins plays an important role in lipoprotein metabolism and cardiovascular disease. Although there have been many valuable studies of HDL binding to tissues, cells and membranes, and of the potential role of such binding in the transport of lipids between HDL and cells, much less is known about HDL receptors than about receptors for other lipoproteins (e.g. LDL, chylomicrons, vitellogenin). Here we review recent studies of the class B, type I scavenger receptor, which appears to be a physiologically relevant, cell surface HDL receptor that mediates the selective uptake of lipids by cells.

The effects of diet on lipoproteins have been studied for many decades. Current research is focused on the effects of individual fatty acids, the extent to which diet influences lipoprotein (a) and the degree to which postprandial lipoprotein metabolism can be influenced. Practical implementation of dietary recommendations aimed at reducing lipoprotein-mediated risk of coronary heart disease remains an important issue.

Dyslipidemia is a powerful risk factor for cardiovascular disease (CVD). Dietary fatty acid composition regulates lipids and lipoprotein metabolism and may confer CVD benefit. This review updates understanding of the effect of dietary fatty acids on lipoprotein metabolism in humans.High dietary fish-derived n-3 polyunsaturated fatty acid (PUFA) consumption diminished hepatic triglyceride-rich lipoprotein (TRL) secretion and enhanced TRL to LDL conversion. n-3 PUFA also decreased TRL-apoB-48 concentration by decreasing TRL-apoB-48 secretion. High n-6 PUFA intake decreased liver fat, and plasma proprotein convertase subtilisin/kexin type 9, triglycerides, total-cholesterol and LDL-cholesterol concentrations. Intake of saturated fatty acids with increased palmitic acid at the sn-2 position was associated with decreased postprandial lipemia, which might be due to decreased triglyceride absorption. Replacing carbohydrate with monounsaturated fatty acids increased TRL catabolism. Ruminant trans-fatty acid decreased HDL cholesterol, but the mechanisms are unknown. A new role for APOE genotype in regulating lipid responses was also described.The major advances in understanding the effect of dietary fatty acids on lipoprotein metabolism have focused on n-3 PUFA. This knowledge provides insights into the importance of regulating lipoprotein metabolism as a mode to improve plasma lipids and potential CVD risk. Further studies are required to better understand the cardiometabolic effects of other dietary fatty acids.

Serum lipoproteins are related to vascular atherosclerotic changes as seen in necropsy studies of child fatal accident victims; therefore, efforts have been made to reveal the determinants of lipoprotein metabolism in children and young adults. Recent data emphasize the adverse effects of obesity, insulin resistance and high fat intake on lipid profiles of children, and currently many lifestyle and dietary intervention studies are in progress. Detection of hereditary dyslipidemias in childhood is presently hampered by diagnostic problems. However, with the advent of efficient tools for genetic mapping, early diagnosis of common genetic dyslipidemias will probably be possible in the near future.

Resistance to insulin-stimulated glucose uptake and to insulin suppression of free fatty acids is related to numerous lipid and lipoprotein abnormalities that increase risk for coronary heart disease. This paper will review recent advances in understanding these associations.

Daily smoking and use of alcohol have a many-fold influence on lipid metabolism. The relations between HDL-cholesterol, alcohol use and smoking are well known. During recent years, the influence of smoking on postprandial lipid and glucose metabolism, and on insulin sensitivity in particular, has gained increasing attention. In addition, new data have emerged about the oxidative properties of alcohol use and smoking. As life habits tend to show clustering, isolating mechanisms responsible for the lipid changes induced by smoking or alcohol per se is difficult and is one factor causing contradiction in this study area.

Dietary fat clearly affects plasma lipid lipoprotein levels. A better understanding of the effect of individual fatty acids on plasma lipoprotein levels has been achieved, although many issues still remain unresolved. Uncertainty with respect to the effects of monounsaturated fatty acids relative to polyunsaturated fatty acids exists. Initial data in primates suggest that dietary fat alters LDL-cholesterol levels via changes in the fractional catabolic and production rates, whereas it alters HDL-cholesterol levels via changes in the fractional catabolic rate.

There are strong epidemiologic connections between plasma triglycerides and atherosclerosis. We will consider to what extent this goes back to derangements of the lipoprotein lipase (LPL) system. The roles of hepatic lipase and endothelial lipase will also be touched upon.Understanding of LPL action has taken major steps with the discovery of lipase maturation factor 1 as a specific endoplasmic reticulum chaperon needed for proper folding of the lipases, glycosylphosphatidylinositol-anchored HDL-binding protein 1 as an endothelial cell protein needed for transport and binding of LPL and some angiopoietin-like proteins that can modulate LPL activity. Studies of genetic variants continue to support the important roles of the lipases in lipoprotein metabolism and in atherosclerosis.There are several ways by which derangement of the lipases may contribute to atherogenesis. Lipase actions are major determinants of plasma lipoprotein patterns. LPL activity must be modulated in relation to the physiological situation (feeding, fasting, exercise, etc.). Fatty acids and monoglycerides generated must be efficiently removed so that they do not endanger the integrity of the endothelium, cause lipotoxic reactions or both. In addition, the lipases may cause binding and endocytosis of lipoprotein particles in the artery wall.

Drinking alcohol has multiple effects on lipoprotein metabolism that lead to alterations, such as low levels of LDL and lipoprotein (a) and high levels of HDL. The protective effects of alcohol against coronary heart disease may be partly mediated by these lipoprotein changes. This review will focus mainly on the mechanisms potentially responsible for the alcohol-induced alterations in lipoprotein metabolism. Some common pitfalls in alcohol studies will also be discussed.

The success of high throughput sequencing programmes, including the Human Genome Project led to the 'identification' of a large number of novel genes of completely unknown function. Since then, many of these genes have been subject to functional studies focussed on uncovering their biological importance. Recent advances in genome-wide screening of DNA sequence variants as well as focussed genetic studies identified a number of candidate loci contributing to the development of complex diseases, including those affecting lipid homeostasis. An excellent example for the convergence of genetics and experimental biology is the tribbles gene family which was among those identified both in recent genetic studies and were implicated in dysregulation of lipid levels experimentally. Thus, there is a need now to take a step back and reconcile these findings accumulated over recent years.Allelic variants of tribbles proteins have been associated with the control of fatty acid synthesis and insulin resistance as well as regulating plasma triglyceride and HDL cholesterol levels. Several mechanisms of molecular action have been proposed for the tribbles mediated control of these processes, including the regulation of signalling events, protein turnover and transcription, sometimes with conflicting evidence emerging.This review attempts to synthesize knowledge obtained on the biology of the tribbles protein family in the context of lipid metabolism as well as discussing the recently emerging genetic evidence for the importance of these proteins in human disease.

Growth hormone (GH) has significant effects on hepatic lipoprotein metabolism, stimulating triglyceride biosynthesis, secretion of VLDL, apolipoprotein (apo)E, and the editing of apoB while simultaneously increasing the expression of LDL receptors. Clinical observations support the concept that GH may have a protective role in the prevention of atherosclerosis, and treatment with GH could thus be beneficial in states of GH deficiency.

Removal of the liver from its physiological environment provides the opportunity to examine its response when challenged directly with substances which, in vivo, are associated with changes in lipid and lipoprotein metabolism. Many in-vitro models are currently available, ranging from intact, perfused livers to transformed cell lines. Selection of the most suitable model depends upon the precise experimental objective(s) and, in most cases, involves trading off one advantage in favour of another. This is particularly true in selecting a human model, and in this case, complementary studies involving more than one model system may provide the best results.

Review literature on the effect of decreasing cholesteryl ester transfer protein (CETP) activity through pharmacological inhibition or modulation in preclinical and clinical settings compared to human CETP deficiency on lipoprotein characteristics, HDL remodelling and function.Torcetrapib, anacetrapib and dalcetrapib inhibited the heterotypic transfer of cholesteryl ester from HDL to LDL and/or VLDL with similar potency, although the potency of dalcetrapib was time dependent. Homotypic transfer of cholesteryl ester from HDL3 to HDL2 via recombinant human CETP was inhibited by torcetrapib and anacetrapib (CETP inhibitors, CETPi) but not by dalcetrapib (CETP modulator, CETPm). In a hamster model of reverse cholesterol transport, only dalcetrapib increased efflux of fecal sterols from macrophages to feces. In clinical studies, dose-responses of CETPi and CETPm demonstrate qualitative and quantitative changes in HDL and LDL particle composition and distribution.Recent studies of the CETPi torcetrapib and anacetrapib and the CETPm dalcetrapib have shown differences in the resulting increase in HDL-cholesterol and in the level of HDL remodelling and potential for effective reverse cholesterol transport. Results from ongoing clinical outcomes studies with anacetrapib and dalcetrapib will clarify the relevance of CETP inhibition versus modulation towards HDL remodelling in the treatment of cardiovascular diseases.

To consider the evidence that PCSK9 has effects on lipoprotein metabolism that are in addition to its role in promoting the degradation of the LDL receptor.Transgenic mice expressing human PCSK9 under physiological control have recently been described. As well as the expected effects on LDL-receptor protein levels in the liver, mice expressing the gain-of-function mutant D374Y secrete more triglyceride than control mice or mice expressing wild-type PCSK9, supporting earlier suggestions that apoB synthesis is increased in hepatocytes expressing D374Y PCSK9 and that patients heterozygous for PCSK9 mutations have increased apoB synthesis. No increase in triglyceride secretion was observed in LDLR mice, suggesting that the effect of PCSK9 on triglyceride secretion is to some extent independent of the LDL receptor. Other recent studies have shown an association between serum PCSK9 concentration and serum triglyceride, but care has to be taken in interpretation of these results as it has also been shown that the level of PCSK9 in human serum shows strong diurnal variation.Understanding the physiology of PCSK9 is important because this protein has become a major new target for lipid lowering therapy.

The roles of HDL and plasma triglyceride concentrations as risk factors for coronary heart disease have attracted increasing attention. One protein, apolipoprotein A-IV (apoA-IV), is involved in the metabolism of both triglycerides and HDL. ApoA-IV has been linked with the hydrolysis of triglyceride-rich lipoproteins and with the interconversion of HDL subfractions. ApoA-IV has also been suggested to participate in several stages of reverse cholesterol transport. Structural and functional alterations of apolipoproteins, caused by a variety of mutations, have been shown to influence lipoprotein metabolism in several ways. Uncertainty about the exact biochemical function of apoA-IV has made the use of genetic apoA-IV variants attractive in evaluating its physiological role.

The use of combination therapy with lipid-lowering agents which have complementary effects on lipoprotein metabolism is an important option for the treatment of severe hyperlipoproteinaemia. This review presents a discussion of recent studies of combination therapy set against the background of existing knowledge in this important therapeutic area.

PURPOSE OF REVIEW: Abundant data in rodents suggest an important role for peroxisomal proliferators-activated receptor-delta (PPARdelta) in regulating skeletal muscle fatty acid oxidation and this has consequences for lipid and lipoprotein metabolism. Considerably less is known in humans and this review will focus on evidence derived from studies of the PPARD gene and pharmacological use of specific PPARdelta agonists. RECENT FINDINGS: Genetic association studies of single-nucleotide polymorphisms in the PPARD gene have only provided negative or conflicting evidence for gross phenotypes such as obesity, hyperlipidaemia and type 2 diabetes. This does not exclude more subtle effects in skeletal muscle metabolic function, but studies of this type need replication. A couple of recent studies using the specific PPARdelta agonist GW501516 suggest potent hypolipidaemic actions, presumably caused by enhanced fat oxidation in skeletal muscle. SUMMARY: Considering the hypolipidaemic effect in humans by PPARdelta agonists, long-term studies are needed to confirm efficacy and safety.

PURPOSE OF REVIEW: Chronic kidney disease is associated with specific alterations of lipoprotein metabolism that may be linked to accelerated atherosclerosis and cardiovascular disease. This review summarizes current knowledge of the pathophysiology of renal dyslipidemia and the therapeutic options. RECENT FINDINGS: The renal dyslipidemia is characterized by accumulation of intact and partially metabolized triglyceride-rich apoB-containing and apoC-containing lipoproteins. Increased concentrations of atherogenic apoC-III rich lipoproteins, the hallmark of renal dyslipidemia, may result from disturbances of insulin metabolism and action in chronic kidney disease. Novel findings strongly suggest that apoC-III triggers a cascade of pro-inflammatory events, which ultimately can result in endothelial dysfunction and vascular damage. Disappointingly, recently reported intervention trials with statins have failed to show any benefit on cardiovascular disease in patients with advanced renal failure. SUMMARY: During recent years, our understanding of the character and biological significance of the dyslipidemia of chronic kidney disease, and its link to cardiovascular disease, has increased. However, our knowledge about its proper management is still very limited.

Epidemiological, clinical and experimental studies consistently indicate that triglyceride-rich lipoproteins influence the activity of coagulation factor VII and the plasma levels o' plasminogen activator inhibitor-1. Lipoprotein (a) may provide a further link between lipoprotein metabolism and fibrinolytic function by interfering with the numerous physiological actions of plasminogen.

Plasma cholesteryl ester transfer protein and phospholipid transfer protein are involved in lipoprotein metabolism. Conceivably, manipulation of either transfer protein could impact atherosclerosis and other lipid-driven diseases.Cholesteryl ester transfer protein mediates direct HDL cholesteryl ester delivery to the liver cells; adipose tissue-specific overexpression of cholesteryl ester transfer protein in mice reduces the plasma HDL cholesterol concentration and adipocyte size; cholesteryl ester transfer protein TaqIB polymorphism is associated with HDL cholesterol plasma levels and the risk of coronary heart disease. In apolipoprotein B transgenic mice, phospholipid transfer protein deficiency enhances reactive oxygen species-dependent degradation of newly synthesized apolipoprotein B via a post-endoplasmic reticulum process, as well as improving the antiinflammatory properties of HDL in mice. Activity of this transfer protein in cerebrospinal fluid of patients with Alzheimer's disease is profoundly decreased and exogenous phospholipid transfer protein induces apolipoprotein E secretion by primary human astrocytes in vitro.Understanding the relationship between lipid transfer proteins and lipoprotein metabolism is expected to be an important frontier in the search for a therapy for atherosclerosis.

Apolipoprotein E has key functions in lipoprotein metabolism, and polymorphisms in the apolipoprotein E gene are associated with distinct lipoprotein patterns. The possibility of gene-nutrient interactions for apolipoprotein E has been addressed in many studies. Although results have generally been mixed, the indications for such an interaction have been more common in studies employing a metabolic challenge. Studies directly designed to examine apolipoprotein E gene-nutrient interactions are needed.

Apolipoprotein (apo)C-I and apoC-III are constituents of HDL and of triglyceride-rich lipoproteins that slow the clearance of triglyceride-rich lipoproteins by a variety of mechanisms. ApoC-I is an inhibitor of lipoprotein binding to the LDL receptor, LDL receptor-related protein, and VLDL receptor. It also is the major plasma inhibitor of cholesteryl ester transfer protein, and appears to interfere directly with fatty acid uptake. ApoC-III also interferes with lipoprotein particle clearance, but its principal role is as an inhibitor of lipolysis, both through the biochemical inhibition of lipoprotein lipase and by interfering with lipoprotein binding to the cell-surface glycosaminoglycan matrix where lipolytic enzymes and lipoprotein receptors reside. Variation in the expression of apoC-III has been credibly documented to have an important role in hypertriglyceridemia. Variation in the expression of apoC-I may also be important for hypertriglyceridemia under certain circumstances.

The association between elevated plasma LDL-cholesterol concentrations and increased risk for heart disease has made the scientific community aware of dietary sources that might effectively reduce plasma cholesterol levels. Several large-scale cohort studies have documented that dietary fiber lowers the risk for coronary heart disease. In addition, there is substantial evidence from randomized controlled clinical trials that a mean reduction of 9% in LDL-cholesterol can be achieved by intake of different sources of soluble fiber. Incorporating fiber sources into our diet may provide a useful adjunct to a low-saturated fat diet, and may have a further beneficial effect for individuals who have mild-to-moderate hypercholesterolemia. The physicochemical properties of soluble fiber result in important modifications in volume, bulk and viscosity in the intestinal lumen, which will alter metabolic pathways of hepatic cholesterol and lipoprotein metabolism, resulting in lowering of plasma LDL-cholesterol.

It has been suggested that the molecular species or structure of the triglyceride, i.e. not only what fatty acids are present but also their relative order in the sn1, 2, or 3 position on the triglyceride, can influence the metabolism of the triglyceride and its fatty acids, including lipoprotein metabolism. One rationale for this possibility assumes that the fatty acid in the sn2 position can be absorbed intact, i.e. as the sn2 monoglyceride, whereas the sn1,3 fatty acids are absorbed as free fatty acids that metabolize independently. Some sn2 monoglyceride might ultimately serve as the backbone for gut or liver phospholipids, exerting downstream influence on lipid metabolism. Experiments that test this hypothesis directly by feeding triglycerides with modified structure during carefully controlled fat intake are few, particularly in humans, but their results tend to support the paradigm.

Despite limitations, animal models continue to provide insight into the etiology of atherosclerosis. Hamsters, guinea-pigs, and domesticated pigs are being used more frequently to address the biochemical bases for the effects of dietary lipids on cholesterol metabolism.