BBA - Molecular and Cell Biology of Lipids (v.1821, #5)

Postprandial metabolism of meal triglyceride in humans by Jennifer E. Lambert; Elizabeth J. Parks (721-726).
The intake of dietary fat above energy needs has contributed to the growing rates of obesity worldwide. The concept of disease development occurring in the fed state now has much support and dysregulation of substrate flux may occur due to poor handling of dietary fat in the immediate postprandial period. The present paper will review recent observations implicating cephalic phase events in the control of enterocyte lipid transport, the impact of varying the composition of meals on subsequent fat metabolism, and the means by which dietary lipid carried in chylomicrons can lead to elevated postprandial non-esterified fatty acid concentrations. This discussion is followed by an evaluation of the data on quantitative meal fat oxidation at the whole body level and an examination of dietary fat clearance to peripheral tissues — with particular attention paid to skeletal muscle and liver given the role of ectopic lipid deposition in insulin resistance. Estimates derived from data of dietary-TG clearance show good agreement with clearance to the liver equaling 8–12% of meal fat in lean subjects and this number appears higher (10–16%) in subjects with diabetes and fatty liver disease. Finally, we discuss new methods with which to study dietary fatty acid partitioning in vivo. Future research is needed to include a more comprehensive understanding of 1) the potential for differential oxidation of saturated versus unsaturated fatty acids which might lead to meaningful energy deficit and whether this parameter varies based on insulin sensitivity, 2) whether compartmentalization exists for diet-derived fatty acids within tissues vs. intracellular pools, and 3) the role of reduced peripheral fatty acid clearance in the development of fatty liver disease. Further advancements in the quantitation of dietary fat absorption and disposal will be central to the development of therapies designed to treat diet-induced obesity. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► We review aspects of postprandial lipid metabolism and fates of dietary fat. ► Gut lipid release is initiated by cephalic events and enhanced by meal consumption. ► Meal composition influences postprandial lipid delivery, storage, and oxidation. ► Spillover of dietary fat contributes to plasma free fatty acid concentrations. ► New technologies will improve estimates of tissue-specific meal fat metabolism.
Keywords: Dietary fatty acid; Postprandial; Triglyceride; Stable isotope; Obesity;

Gut triglyceride production by Xiaoyue Pan; M. Mahmood Hussain (727-735).
Our knowledge of how the body absorbs triacylglycerols (TAG) from the diet and how this process is regulated has increased at a rapid rate in recent years. Dietary TAG are hydrolyzed in the intestinal lumen to free fatty acids (FFA) and monoacylglycerols (MAG), which are taken up by enterocytes from their apical side, transported to the endoplasmic reticulum (ER) and resynthesized into TAG. TAG are assembled into chylomicrons (CM) in the ER, transported to the Golgi via pre-chylomicron transport vesicles and secreted towards the basolateral side. In this review, we mainly focus on the roles of key proteins involved in uptake and intracellular transport of fatty acids, their conversion to TAG and packaging into CM. We will also discuss intracellular transport and secretion of CM. Moreover, we will bring to light few factors that regulate gut triglyceride production. Furthermore, we briefly summarize pathways involved in cholesterol absorption. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Dietary triacylglycerols are hydrolyzed in the intestine and products are taken up by enterocytes. ► Enterocytes re-synthesize lipids, package them into chylomicrons for secretion. ► Intracellular transport of chylomicrons from the Golgi to plasma membrane is poorly understood.
Keywords: ApoB; Lipid Metabolism; Fat absorption; Fatty acid; MTP; Chylomicron;

Regulation of chylomicron production in humans by Changting Xiao; Gary F. Lewis (736-746).
Chylomicrons (CM), secreted by the intestine in response to fat ingestion and to a lesser extent during the postabsorptive state (lipid poor CM), are the major vehicles whereby ingested lipids are transported to and partitioned in energy-storing and energy-utilizing tissues of the body. CM contribute significantly, although not exclusively, to postprandial lipemia. Intestinal CM production is upregulated in humans under conditions of insulin resistance and CM overproduction in such conditions contributes to the highly prevalent dyslipidemia of these conditions. In addition, CM remnants possess direct atherogenic properties. CM assembly and secretion is regulated by many factors apart from ingested fat (the primary stimulus for their secretion), including a number of nutritional, hormonal, metabolic and genetic factors. Understanding the mechanisms that regulate CM production in health and disease may lead to treatments and prevention of atherosclerosis and cardiovascular disease. This review aims to summarize current understanding of CM production in humans. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Advances in the understanding of chylomicron production in humans are reviewed. ► Chylomicron production is regulated by hormones, FFA, nutrients and lifestyle. ► Overproduction in insulin resistance may contribute to increased CVD risk. ► Pharmacological interventions and genetic factors are discussed.
Keywords: Chylomicron; Apolipoprotein B-48; Human;

Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger? by Anne P.L. Jensen-Urstad; Clay F. Semenkovich (747-753).
Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids. In the liver, FAS has long been categorized as a housekeeping protein, producing fat for storage of energy when nutrients are present in excess. Most previous studies of FAS regulation have focused on the control of gene expression. However, recent findings suggest that hepatic FAS may also be involved in signaling processes that include activation of peroxisome proliferator-activated receptor α (PPARα). Moreover, reports of rapid alterations in FAS activity as well as findings of post-translational modifications of the FAS protein support the notion that dynamic events in addition to transcription impact FAS regulation. These results indicate that FAS enzyme activity can impact liver physiology through signaling as well as energy storage and that its regulation may be complex. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Fatty acid synthase (FAS) produces lipids for energy storage and membrane integrity. ► FAS also has signaling functions that include activation of PPARalpha. ► Both transcriptional as well as post‐translational mechanisms regulate FAS.
Keywords: Lipid signaling; PPARα; Post-translational regulation; Obesity; Fatty liver; Diabetes;

Phosphatidylcholine biosynthesis and lipoprotein metabolism by Laura K. Cole; Jean E. Vance; Dennis E. Vance (754-761).
Phosphatidylcholine (PC) is the major phospholipid component of all plasma lipoprotein classes. PC is the only phospholipid which is currently known to be required for lipoprotein assembly and secretion. Impaired hepatic PC biosynthesis significantly reduces the levels of circulating very low density lipoproteins (VLDLs) and high density lipoproteins (HDLs). The reduction in plasma VLDLs is due in part to impaired hepatic secretion of VLDLs. Less PC within the hepatic secretory pathway results in nascent VLDL particles with reduced levels of PC. These particles are recognized as being defective and are degraded within the secretory system by an incompletely defined process that occurs in a post-endoplasmic reticulum compartment, consistent with degradation directed by the low-density lipoprotein receptor and/or autophagy. Moreover, VLDL particles are taken up more readily from the circulation when the PC content of the VLDLs is reduced, likely due to a preference of cell surface receptors and/or enzymes for lipoproteins that contain less PC. Impaired PC biosynthesis also reduces plasma HDLs by inhibiting hepatic HDL formation and by increasing HDL uptake from the circulation. These effects are mediated by elevated expression of ATP-binding cassette transporter A1 and hepatic scavenger receptor class B type 1, respectively. Hepatic PC availability has recently been linked to the progression of liver and heart disease. These findings demonstrate that hepatic PC biosynthesis can regulate the amount of circulating lipoproteins and suggest that hepatic PC biosynthesis may represent an important pharmaceutical target. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Phosphatidylcholine biosynthesis is required for VLDL secretion. ► Nascent VLDLs deficient in phosphatidylcholine are degraded post-ER. ► Impaired phosphatidylcholine biosynthesis inhibits HDL formation in the liver. ► Hepatic phosphatidylcholine biosynthesis regulates plasma lipoproteins.
Keywords: Liver; Lipoprotein; Phosphatidylcholine; Apo B;

Liver triacylglycerol lipases by Ariel D. Quiroga; Richard Lehner (762-769).
The hallmark of obesity and one of the key contributing factors to insulin resistance, type 2 diabetes and cardiovascular disease is excess triacylglycerol (TG) storage. In hepatocytes, excessive accumulation of TG is the common denominator of a wide range of clinicopathological entities known as nonalcoholic fatty liver disease, which can eventually progress to cirrhosis and associated complications including hepatic failure, hepatocellular carcinoma and death. A tight regulation between TG synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent lipid accumulation as well as lipid depletion from hepatocytes. Therefore, understanding the pathways that regulate hepatic TG metabolism is crucial for development of therapies to ameliorate pathophysiological conditions associated with excessive hepatic TG accumulation, including dyslipidemias, viral infection and atherosclerosis. This review highlights the physiological roles of liver lipases that degrade TG in cytosolic lipid droplets, endoplasmic reticulum, late endosomes/lysosomes and along the secretory route. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Hepatic steatosis is a common liver pathology. ► This review summarizes the current knowledge of hepatic triacylglycerol degradation. ► Specific metabolic functions of hepatic lipases are discussed.
Keywords: Lipase; Hepatic steatosis; Triacylglycerol; Carboxylesterase; Arylacetamide deacetylase; Autophagy; Lipophagy;

Hepatic ABCA1 and VLDL triglyceride production by Mingxia Liu; Soonkyu Chung; Gregory S. Shelness; John S. Parks (770-777).
Elevated plasma triglyceride (TG) and reduced high density lipoprotein (HDL) concentrations are prominent features of metabolic syndrome (MS) and type 2 diabetes (T2D). Individuals with Tangier disease also have elevated plasma TG concentrations and a near absence of HDL, resulting from mutations in ATP binding cassette transporter A1 (ABCA1), which facilitates the efflux of cellular phospholipid and free cholesterol to assemble with apolipoprotein A-I (apoA-I), forming nascent HDL particles. In this review, we summarize studies focused on the regulation of hepatic very low density lipoprotein (VLDL) TG production, with particular attention on recent evidence connecting hepatic ABCA1 expression to VLDL, LDL, and HDL metabolism. Silencing ABCA1 in McArdle rat hepatoma cells results in diminished assembly of large (> 10 nm) nascent HDL particles, diminished PI3 kinase activation, and increased secretion of large, TG-enriched VLDL1 particles. Hepatocyte-specific ABCA1 knockout (HSKO) mice have a similar plasma lipid phenotype as Tangier disease subjects, with a two-fold elevation of plasma VLDL TG, 50% lower LDL, and 80% reduction in HDL concentrations. This lipid phenotype arises from increased hepatic secretion of VLDL1 particles, increased hepatic uptake of plasma LDL by the LDL receptor, elimination of nascent HDL particle assembly by the liver, and hypercatabolism of apoA-I by the kidney. These studies highlight a novel role for hepatic ABCA1 in the metabolism of all three major classes of plasma lipoproteins and provide a metabolic link between elevated TG and reduced HDL levels that are a common feature of Tangier disease, MS, and T2D. This article is part of a Special Issue entitled: Triglyceride Metabolism and Disease.► Hepatic VLDL overproduction is a prominent cause of elevated plasma TGs. ► Loss of hepatic ABCA1 expression leads to VLDL1 overproduction. ► Loss of hepatic ABCA1 results in plasma LDL hypercatabolism. ► Hepatic ABCA1 affects metabolism of all major plasma lipoprotein classes.
Keywords: Tangier disease; Metabolic syndrome; Type 2 diabetes; Nascent HDL; PI3 kinase; VLDL1;

Very low density lipoproteins (VLDL) are a major secretory product of the liver. They serve to transport endogenously synthesized lipids, mainly triglycerides (but also some cholesterol and cholesteryl esters) to peripheral tissues. VLDL is also the precursor of LDL. ApoB100 is absolutely required for VLDL assembly and secretion. The amount of VLDL triglycerides secreted by the liver depends on the amount loaded onto each lipoprotein particle, as well as the number of particles. Each VLDL has one apoB100 molecule, making apoB100 availability a key determinant of the number of VLDL particles, and hence, triglycerides, that can be secreted by hepatic cells. Surprisingly, the pool of apoB100 in the liver is typically regulated not by its level of synthesis, which is relatively constant, but by its level of degradation. It is now recognized that there are multiple opportunities for the hepatic cell to intercept apoB100 molecules and to direct them to distinct degradative processes. This mini-review will summarize progress in understanding these processes, with an emphasis on autophagy, the most recently described pathway of apoB100 degradation, and the one with possibly the most physiologic relevance to common metabolic perturbations affecting VLDL production. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Hepatic apolipoprotein B100 (apoB100) is subject to multiple pathways of degradation. ► Degradation of apoB100 determines the number of TG-rich VLDL particles secreted. ► Degradative pathways include ER-associated and post-ER proteolysis (PERPP). ► ApoB100 PERPP is mediated by autophagy in some cases (e.g., with fish oils). ► Autophagic PERPP may underlie sortillin-1 and insulin-mediated apoB100 degradation.
Keywords: VLDL; Apolipoprotein B; Autophagy; ER-associated degradation; Liver; Triglyceride;

Regulation of triglyceride metabolism by Angiopoietin-like proteins by Frits Mattijssen; Sander Kersten (782-789).
Plasma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Genetic variation in ANGPTLs impacts circulating TG levels in humans. ► ANGPTL3 and -4 are potent inhibitors of LPL via multiple mechanisms. ► ANGPTL3 and -4 are subject to many post-translational modifications. ► Expression of ANGPTL3 and -4 is governed by oxysterols and fatty acids, respectively.
Keywords: Angiopoietin-like proteins; Triglycerides; Lipoprotein lipase; PPARs;

Mutations in lipase maturation factor 1 (LMF1) are associated with severe hypertriglyceridemia in mice and human subjects. The underlying cause is impaired lipid clearance due to lipase deficiency. LMF1 is a chaperone of the endoplasmic reticulum (ER) and it is critically required for the post-translational activation of three vascular lipases: lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL). As LMF1 is only required for the maturation of homodimeric, but not monomeric, lipases, it is likely involved in the assembly of inactive lipase subunits into active enzymes and/or the stabilization of active dimers. Herein, we provide an overview of current understanding of LMF1 function and propose that it may play a regulatory role in lipase activation and lipid metabolism. Further studies will be required to test this hypothesis and elucidate the full spectrum of phenotypes in combined lipase deficiency. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.Display Omitted► Mutations in LMF1 cause lipase deficiency and hypertriglyceridemia. ► LMF1 is an ER chaperone. ► LMF1 is required for the post-translational activation of LPL, HL and EL.
Keywords: Lipase maturation factor; Lipoprotein lipase; Hepatic lipase; Endothelial lipase; Hypertriglyceridemia;

Apolipoprotein A-V dependent modulation of plasma triacylglycerol: A puzzlement by Vineeta Sharma; Robert O. Ryan; Trudy M. Forte (795-799).
The discovery of apolipoprotein A-V (apoA-V) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome wide association studies (GWAS) have consistently identified APOA5 as a contributor to plasma TG levels. Single nucleotide polymorphisms (SNP) within the APOA5 gene locus have been shown to correlate with elevated plasma TG. Furthermore, transgenic and knockout mouse models support the view that apoA-V plays a critical role in maintenance of plasma TG levels. The present review describes recent concepts pertaining to apoA-V SNP analysis and their association with elevated plasma TG. The interaction of apoA-V with glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) is discussed relative to its postulated role in TG-rich lipoprotein catabolism. The potential role of intracellular apoA-V in regulation of TG homeostasis, as a function of its ability to associate with cytosolic lipid droplets, is reviewed. While some answers are emerging, numerous mysteries remain with regard to this low abundance, yet potent, modulator of TG homeostasis. Given the strong correlation between elevated plasma TG and heart disease, there is great scientific and public interest in deciphering the numerous biological riddles presented by apoA-V. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Genome wide association studies identify APOA5 as a contributor to plasma TG. ► Single nucleotide polymorphisms (SNP) in APOA5 correlate with elevated plasma TG. ► ApoA-V SNP analysis and their association with elevated plasma TG. ► Interaction of apoA-V with GPIHBP1 and apoA-V binding to lipid droplets. ► The correlation between TG and heart disease has intensified interest in apoA-V.
Keywords: Apolipoprotein A-V; Triglyceride; Lipid droplet; Genome wide association study; Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1; Nonalcoholic fatty liver disease;

Although cardiovascular disease is the leading cause of diabetes-related death, its etiology is still not understood. The immediate change that occurs in the diabetic heart is altered energy metabolism where in the presence of impaired glucose uptake, glycolysis, and pyruvate oxidation, the heart switches to exclusively using fatty acids (FA) for energy supply. It does this by rapidly amplifying its lipoprotein lipase (LPL—a key enzyme, which hydrolyzes circulating lipoprotein-triglyceride to release FA) activity at the coronary lumen. An abnormally high capillary LPL could provide excess fats to the heart, leading to a number of metabolic, morphological, and mechanical changes, and eventually to cardiac disease. Unlike the initial response, chronic severe diabetes “turns off” LPL, this is also detrimental to cardiac function. In this review, we describe a number of post-translational mechanisms that influence LPL vesicle formation, actin cytoskeleton rearrangement, and transfer of LPL from cardiomyocytes to the vascular lumen to hydrolyze lipoprotein-triglyceride following diabetes. Appreciating the mechanism of how the heart regulates its LPL following diabetes should allow the identification of novel targets for therapeutic intervention, to prevent heart failure. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► LPL is a key provider of fatty acids to the heart following diabetes. ► We describe mechanisms by which vascular LPL is regulated following diabetes. ► Perturbations in LPL contribute to the pathology of diabetic cardiomyopathy.
Keywords: LPL; Card iomyocyte; Diabetes; Heart metabolism;

Roles of PPARs in NAFLD: Potential therapeutic targets by Anne Tailleux; Kristiaan Wouters; Bart Staels (809-818).
Non-alcoholic fatty liver disease (NAFLD) is a liver pathology with increasing prevalence due to the obesity epidemic. Hence, NAFLD represents a rising threat to public health. Currently, no effective treatments are available to treat NAFLD and its complications such as cirrhosis and liver cancer. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. Here we review recent findings on the pathophysiological role of PPARs in the different stages of NAFLD, from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidence for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis toward irreversible, more advanced lesions. Presently, large controlled trials of long duration are needed to assess the long-term clinical benefits of PPAR agonists in humans. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► NASH and NAFLD are an increasing threat to public health. ► No effective treatments are available. ► PPARs are regulators of lipid metabolism and inflammation. ► We review the recent studies in preclinical models. ► We discuss the clinical use of PPARs to treat NAFLD and NASH in humans.
Keywords: NASH; NAFLD; PPARs; Preclinical model; Clinical trial;

Hypertriglyceridemia secondary to obesity and diabetes by Savitha Subramanian; Alan Chait (819-825).
Hypertriglyceridemia is a common lipid abnormality in persons with visceral obesity, metabolic syndrome and type 2 diabetes. Hypertriglyceridemia typically occurs in conjunction with low HDL levels and atherogenic small dense LDL particles and is associated with increased cardiovascular risk. Insulin resistance is often an underlying feature and results in increased free fatty acid (FFA) delivery to the liver due to increased peripheral lipolysis. Increased hepatic VLDL production occurs due to increased substrate availability via FFAs, decreased apolipoprotein B100 degradation and increased lipogenesis. Postprandial hypertriglyceridemia also is a common feature of insulin resistance. Small dense LDL that coexist with decreased HDL particles in hypertriglyceridemic states are highly pro-atherogenic due to their enhanced endothelial permeability, proteoglycan binding abilities and susceptibility to oxidation. Hypertriglyceridemia also occurs in undertreated individuals with type 1 diabetes but intensive glucose control normalizes lipid abnormalities. However, development of visceral obesity in these patients unravels a similar metabolic profile as in patients with insulin resistance. Modest hypertriglyceridemia increases cardiovascular risk, while marked hypertriglyceridemia should be considered a risk for pancreatitis. Lifestyle modification is an important therapeutic strategy. Drug therapy is primarily focused on lowering LDL levels with statins, since efforts at triglyceride lowering and HDL raising with fibrates and/or niacin have not yet been shown to be beneficial in improving cardiovascular risk. Fibrates, however, are first-line agents when marked hypertriglyceridemia is present. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Low HDL and increased small dense LDL accompany hypertriglyceridemia of obesity. ► Increased FFA flux to the liver and increased apo B production are contributory. ► Management involves lifestyle changes with drug therapy to lower LDL cholesterol.
Keywords: Visceral obesity; Insulin resistance; Free fatty acids; VLDL overproduction; Small dense LDL;

Pathophysiology of hypertriglyceridemia by H.C. Hassing; R.P. Surendran; H.L. Mooij; E.S. Stroes; M. Nieuwdorp; G.M. Dallinga-Thie (826-832).
The importance of triglycerides as risk factor for CVD is currently under debate. The international guidelines do not include TG into their risk calculator despite the recent observations that plasma TG is an independent risk factor for CVD. The understanding of the pathophysiology of triglycerides opens up avenues for development of new drug targets. Hypertriglyceridemia occurs through 1. Abnormalities in hepatic VLDL production, and intestinal chylomicron synthesis 2. Dysfunctional LPL-mediated lipolysis or 3. Impaired remnant clearance. The current review will discuss new aspects in lipolysis by discussing the role of GPIHBP1 and the involvement of apolipoproteins and in the process of hepatic remnant clearance with a focus upon the role of heparin sulfate proteoglycans. Finally we will shortly discuss future perspectives for novel therapies aiming at improving triglyceride homeostasis. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Peripheral lipolysis is dependent upon GPIHBP1 and LPL. ► The role of HSPG is limited. ► The role of apoAV in peripheral lipolysis remains to be elucidated. ► Hepatic remnant clearance involves receptor-mediated uptake through LDLr, LRP1 or HSPG. ► Modulating factors resulting in hepatic loss of function of HSPG lead to impaired hepatic TG clearance.
Keywords: Triglyceride; Cardiovascular disease; LPL; GPIHBP1; LMF1;

Allelic and phenotypic spectrum of plasma triglycerides by Christopher T. Johansen; Robert A. Hegele (833-842).
The genetic underpinnings of both normal and pathological variation in plasma triglyceride (TG) concentration are relatively well understood compared to many other complex metabolic traits. For instance, genome-wide association studies (GWAS) have revealed 32 common variants that are associated with plasma TG concentrations in healthy epidemiologic populations. Furthermore, GWAS in clinically ascertained hypertriglyceridemia (HTG) patients have shown that almost all of the same TG-raising alleles from epidemiologic samples are also associated with HTG disease status, and that greater accumulation of these alleles reflects the severity of the HTG phenotype. Finally, comprehensive resequencing studies show a burden of rare variants in some of these same genes – namely in LPL, GCKR, APOB and APOA5 – in HTG patients compared to normolipidemic controls. A more complete understanding of the genes and genetic variants associated with plasma TG concentration will enrich our understanding of the molecular pathways that modulate plasma TG metabolism, which may translate into clinical benefit. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► GWAS have identified 32 loci associated with plasma TG concentration. ► The same genetic determinants of ‘normal’ TG also underlie extreme TG phenotypes. ► A balance of common and rare small effect variants gives rise to “normal” TG. ► Common small effect and rare heterozygous large effect variants accumulate in polygenic HTG and hypoTG. ► Homozygous large effect variants give rise to monogenic HTG and hypoTG.
Keywords: Genetic variation; Rare variant; Resequencing; Hypertriglyceridemia; Triglyceride metabolism; Lipoprotein;

Fish oil — How does it reduce plasma triglycerides? by Gregory C. Shearer; Olga V. Savinova; William S. Harris (843-851).
Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels. At the pharmaceutical dose, 3.4 g/day, they reduce plasma TG by about 25–50% after one month of treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Pharmaceutical long chain omega-3 fatty acids effectively reduce plasma triglyceride levels. ► Fish oil reduces the rate of VLDL synthesis in the liver. ► Reduced NEFA delivery to the liver is a likely locus of action for fish oils. ► Fish oil counteracts the lipolytic release of NEFA from adipose tissue by suppressing inflammation. ► Fish oil increases FA uptake and β-oxidation in adipose, heart and skeletal muscle.
Keywords: Fish oil; Omega-3; Plasma triglyceride; Lipolysis; NEFA; VLDL;

Fatty acid transport proteins, implications in physiology and disease by Melissa Kazantzis; Andreas Stahl (852-857).
Uptake of long-chain fatty acids plays pivotal roles in metabolic homeostasis and human physiology. Uptake rates must be controlled in an organ-specific fashion to balance storage with metabolic needs during transitions between fasted and fed states. Many obesity-associated diseases, such as insulin resistance in skeletal muscle, cardiac lipotoxicity, and hepatic steatosis, are thought to be driven by the overflow of fatty acids from adipose stores and the subsequent ectopic accumulation of lipids resulting in apoptosis, ER stress, and inactivation of the insulin receptor signaling cascade. Thus, it is of critical importance to understand the components that regulate the flux of fatty acid between the different organ systems. Cellular uptake of fatty acids by key metabolic organs, including the intestine, adipose tissue, muscle, heart, and liver, has been shown to be protein mediated and various unique combinations of fatty acid transport proteins (FATPs/SLC27A1–6) are expressed by all of these tissues. Here we review our current understanding of how FATPs can contribute to normal physiology and how FATP mutations as well as hypo- and hypermorphic changes contribute to disorders ranging from cardiac lipotoxicity to hepatosteatosis and ichthyosis. Ultimately, our increasing knowledge of FATP biology has the potential to lead to the development of new diagnostic tools and treatment options for some of the most pervasive chronic human disorders. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Physiological fatty acids fluxes and Slc27 members. ► FATP transport mechanism/subcellular localization. ► Contribution of FATPs to insulin resistance and cardiovascular disease. ► Role of FATP4 in skin and hepatobiliary disorders. ► Polymorphisms and mutations in human FATP genes.
Keywords: Fatty acid uptake protein; SLC27; Diabetes; Lipotoxicity; Hepatosteatosis; Ichthyosis;

Epidemiological and interventional studies have implicated elevated triglyceride-rich lipoprotein (TGRL) levels as a risk factor for cardiovascular disease and vascular inflammation, though the results have not been entirely consistent. This appears particularly relevant in model systems where the lipolysis occurs in the setting of established inflammation (e.g., in pre-existing atherosclerotic plaques), rather than in the tissue capillary beds where lipolysis normally occurs. Two main mechanisms seem to link TGRL lipolysis to vascular inflammation. First, lipolysis of TGRL leaves behind partially lipolyzed remnant particles which are better able to enter the vessel wall than nascent TGRL, have a rate of egress substantially lower than their rate of entry, and contain 5–20 times more cholesterol per particle than LDL. Furthermore, remnants do not require oxidation or other modifications to be phagocytized by macrophages, enhancing foam cell formation. Second, saturated fatty acids and oxidized phospholipids released by lipolysis induce inflammation by activating Toll-like receptors of the innate immune system, via oxidative stress, or by greatly amplifying existing pro-inflammatory signals (caused by subclinical endotoxemia) via mitogen-activated protein kinases. However, n-3 and unbound n-9 unsaturated fatty acids released by lipolysis have anti-inflammatory effects. Thus, the contribution of TGRL lipolysis to inflammation likely depends less on the TGRL concentration than on the balance between pro- and anti-inflammatory factors, and on the setting in which the lipolysis occurs. In the setting of the typical “Western” diet, enriched in saturated and oxidized fatty acids and excessive in size, this balance is likely to be tilted towards increased vascular inflammation and atherosclerosis. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Lipolysis of triglyceride-rich lipoproteins creates remnant particles. ► Remnant particles are more efficient sources of foam cell cholesterol than LDL. ► Saturated or oxidized fatty acids also induce inflammation. ► However, n-3 or unbound n-9 unsaturated fatty acids may be anti-inflammatory. ► Balance between pro- and anti-inflammatory factors matters more than concentration.
Keywords: Chylomicrons; VLDL; Remnant-like particles; Lipoprotein lipase; Free fatty acids; Atherosclerosis;

Serum triglycerides and risk of cardiovascular disease by A.C.I. Boullart; J. de Graaf; A.F. Stalenhoef (867-875).
Dyslipidemia, especially elevated serum levels of cholesterol, is causally related to cardiovascular disease. The specific role of triglycerides has long been controversial. In this article we discuss the role of serum triglycerides in relation to the risk of cardiovascular disease. First, the (patho)physiology of triglycerides is described, including the definition and a short summary of the primary and secondary causes of hypertriglyceridemia. Furthermore, we will give an overview of the published epidemiological studies concerning hypertriglyceridemia and cardiovascular disease to support the view that triglyceride-rich lipoproteins are an independently associated risk factor. Finally, treatment strategies and treatment targets are discussed. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.► Triglycerides can be increased by hepatic oversecretion and/or impaired removal. ► Environmental factors can induce severe hypertriglyceridemia. ► Non-HDL-cholesterol or apoB should be targets for cardiovascular risk management. ► The value of fibrates must be tested in the right selected patient groups.
Keywords: Triglyceride; Hypertriglyceridemia; Metabolism; Lipid lowering drug; Cardiovascular disease;