Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide ( 1 ). Dyslipidemia has been shown to be one of the most potent risk factors for coronary heart disease (CHD) ( 2, 3 ). Dyslipidemia is characterized by elevated plasma cholesterol, especially low density lipoprotein cholesterol (LDL-c) levels. Management of dyslipidemia is considered throughout the primary and secondary prevention of CHD ( 4 ). For the past 20 years, the statin (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) class of cholesterol-lowering drugs has been used for the treatment of hypercholesterolemia, either alone or in combination with other classes of lipid-lowering drugs Abstract In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profi les in 24 models. These included fi ve mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profi les, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study . -

These results reveal for the first time that resistin is a highly attractive therapeutic target in ameliorating elevated serum low-density lipoprotein and, thereby, atherosclerotic cardiovascular diseases in obese humans.

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters. In contrast, experiments in primary human, rhesus, and cynomolgus hepatocytes demonstrated that selective inhibition of DGAT2 has only a modest effect. Acute and chronic inhibition of DGAT2 in rhesus primates recapitulated the in vitro data yielding no significant effects on production of plasma TG or VLDL apolipoprotein B. These results call into question whether selective inhibition of DGAT2 is sufficient for remediation of dyslipidemia.

It has been proposed that clearance of cholesterolenriched very low density lipoprotein (VLDL) particles occurs through a multistep process beginning with their initial binding to cell-surface heparan sulfate proteoglycans (HSPG), followed by their uptake into cells by a receptor-mediated process that utilizes members of the low density lipoprotein receptor (LDLR) family, including the low density lipoprotein receptor-related protein (LRP). We have further explored the relationship between HSPG binding of VLDL and its subsequent internalization by focusing on the LRP pathway using a cell line deficient in LDLR. In this study, we show that LRP and HSPG are part of a co-immunoprecipitable complex at the cell surface demonstrating a novel association for these two cell surface receptors. Cell surface binding assays show that this complex can be disrupted by an LRP-specific ligand binding antagonist, which in turn leads to increased VLDL binding and degradation. The increase in VLDL binding results from an increase in the availability of HSPG sites as treatment with heparinase or competitors of glycosaminoglycan chain addition eliminated the augmented binding. From these results we propose a model whereby LRP regulates the availability of VLDL binding sites at the cell surface by complexing with HSPG. Once HSPG dissociates from LRP, it is then able to bind and internalize VLDL independent of LRP endocytic activity. We conclude that HSPG and LRP together participate in VLDL clearance by means of a synergistic relationship. Remnant lipoproteins originating from lipolytic processing of dietary chylomicrons and very low density lipoproteins (VLDL)1 synthesized by the liver are primary carriers in lipid transport and facilitate the delivery of cholesterol and triglycerides to hepatic and extrahepatic tissues. VLDL particles consist of apolipoprotein B (apoB) and apolipoproteins CI, CII, and CIII (1) with esterified cholesterol and triglycerides at their core, and an outer association of apolipoprotein E (apoE). Apo-CII is thought to activate lipoprotein lipase, necessary for lipolytic processing (2-4). ApoB (5, 6) and apoE (7,8) are required for receptor-mediated clearance of VLDL particles.Receptor-mediated clearance of circulating VLDL is a rapid and critical step for maintenance of proper plasma lipid levels. The half-life of injected VLDL is reported to be ϳ20 min in mice and rabbits (9). Elevated VLDL levels, as seen in type III hyperlipoproteinemia (10, 11), lead to elevated plasma triglyceride levels making VLDL highly atherogenic (5). Moreover, excessive VLDL uptake by macrophages results in cholesterol accumulation and foam cell formation (12, 13) increasing the risk for coronary heart disease and stroke.Clearance of VLDL is thought to occur through a multistep process. VLDL initially binds to cell surfaces through interactions with heparan sulfate proteoglycans (HSPG) (14), and this binding is mediated by apoE, which contains a high affinity heparan sulfate binding site (15, 16). Accordingly, apoE knockout mice...

Our ability to understand the pathogenesis of problems surrounding lipid accretion requires attention towards quantifying lipid kinetics. In addition, studies of metabolic flux should also help unravel mechanisms that lead to imbalances in inter-organ lipid trafficking which contribute to dyslipidemia and/or peripheral lipid accumulation (e.g. hepatic fat deposits). This review aims to outline the development and use of novel methods for studying lipid kinetics in vivo. Although our focus is directed towards some of the approaches that are currently reported in the literature, we include a discussion of the older literature in order to put "new" methods in better perspective and inform readers of valuable historical research. Presumably, future advances in understanding lipid dynamics will benefit from a careful consideration of the past efforts, where possible we have tried to identify seminal papers or those that provide clear data to emphasize essential points. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.