Showing papers on "Endothelial lipase published in 2004"

High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease.

Abstract: Purpose of review Low HDL-cholesterol, diabetes mellitus and elevated C-reactive protein as well as various inflammatory diseases are risk factors for coronary heart disease. Both diabetes mellitus and inflammation decrease HDL-cholesterol. We summarize recent findings on the mechanisms underlying low HDL-cholesterol in diabetes and inflammation, as well as on novel functions of HDL that may protect not only from atherosclerosis but also from diabetes mellitus and inflammation-induced organ damage. Recent findings Elevated levels of non-esterified fatty acids and disturbed insulin action contribute to low HDL-cholesterol in diabetes mellitus by modifying lipolysis, apolipoprotein A-I production, as well as the activities of adenosine triphosphate-binding cassette transporter A1 and lipid transfer. Inflammation causes low HDL-cholesterol by increasing the activities of endothelial lipase and soluble phospholipase A2 and by replacing apolipoprotein A-I in HDL with serum amyloid A. HDL and lysosphingolipids therein have been identified as activators of the protein kinase Akt, which in turn is a regulator of apoptosis in beta-cells, endothelial cells, and smooth muscle cells, as well as a regulator of nitric oxide production and adhesion molecule expression in endothelial cells. Summary The protective properties of HDL in cytokine production, lipid oxidation, cholesterol efflux and reverse cholesterol transport make HDL a protective agent in inflammation-induced organ damage including diabetes mellitus. However, inflammation and diabetes cause a decrease in HDL-cholesterol concentrations and impair HDL function, placing HDL into the centre of a vicious cycle that may escalate into diabetes mellitus, inflammation-induced organ damage and atherosclerosis.

Lipoprotein lipase and its role in regulation of plasma lipoproteins and cardiac risk.

Abstract: For over 50 years, biologists and clinicians have studied lipoprotein lipase (LPL) and learned about its structure, function, cellular production, physiology, and human genetics. LPL is the principal enzyme that removes triglyceride from the bloodstream. It also determines plasma levels of high-density lipoprotein. Surprisingly, within the past several years, a number of new and unexpected proteins have been discovered that regulate the actions of LPL. These include the very low-density lipoprotein receptor, angiopoetin-like protein 3, and apolipoprotein A-V. In addition, mouse genetic studies have confirmed tissue culture findings of nonenzymatic roles of LPL both in lipid metabolism and atherogenesis. These basic observations are now being related to new information on human genetic polymorphism in this gene that is likely to affect clinical evaluation of lipoprotein disorders and cardiac risk.

Endothelial Lipase Promotes the Catabolism of ApoB-Containing Lipoproteins

Abstract: Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are “HDL animals” and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor–deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (EL S149A ); unexpectedly, expression of EL S149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive EL S149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.

Endothelial lipase and HDL metabolism.

Abstract: Purpose of review In the past year, several laboratories taking independent approaches have provided compelling evidence that endothelial lipase, a relatively recent addition to the triglyceride lipase gene family, is a major determinant of HDL metabolism. This review summarizes recent findings from experiments in mice with altered levels of endothelial lipase, from an examination of endothelial lipase catalytic and non-catalytic functions in vitro, and from human genetic studies. Recent findings An analysis of lipids and lipoproteins in endothelial lipase knockout and transgenic mice and in mice with adenovirus-driven hepatic overexpression of endothelial lipase shows, without exception, that total cholesterol, phospholipid and HDL-cholesterol all vary inversely with the endothelial lipase gene dosage, and primarily depend on endothelial lipase catalytic activity. Endothelial lipase participates in HDL metabolism by promoting the turnover of HDL components and increasing the catabolism of apolipoprotein A-I. The measurement of lipase activity on lipoprotein substrates in vitro demonstrates that endothelial lipase is distinct from other triglyceride lipases in showing the highest activity on HDL. Endothelial lipase gene polymorphisms in humans appear to be associated with HDL-cholesterol or HDL3-cholesterol concentrations. Summary A low HDL-cholesterol level in humans is a risk factor for coronary heart disease. Although not yet demonstrated, it is possible that the action of endothelial lipase on HDL may promote atherogenesis, in which case endothelial lipase may represent an attractive target for pharmaceutical intervention.

The role of endothelial lipase in high-density lipoprotein metabolism.

Abstract: Purpose of reviewElevating high-density lipoprotein levels is increasingly being identified as an essential strategy for the prevention of atherosclerosis. Plasma levels of high-density lipoprotein cholesterol and its major protein, apoAI, are largely influenced by the rate of turnover. Lipases play

Differential Additive Effects of Endothelial Lipase and Scavenger Receptor-Class B Type I on High-Density Lipoprotein Metabolism in Knockout Mouse Models

Abstract: Objective— Endothelial lipase (EL) is a vascular phospholipase that hydrolyzes high-density lipoprotein (HDL) as its preferred substrate. Scavenger receptor-class B type I (SR-BI) is an HDL receptor that mediates the selective uptake of cholesteryl ester. This study investigates the role of EL and SR-BI in the regulation of HDL metabolism in gene knockout mouse models. Methods and Results— We cross-bred EL−/− and SR-BI−/− mice and generated single- and double-null mice. We used biochemical, molecular biology, and nuclear magnetic resonance methods to analyze HDL concentration, composition, and structure. We found that EL and SR-BI display additive effects on HDL with evident gene dosage effects, but their mechanisms to regulate HDL concentration and composition are different. Whereas the elevated HDL cholesterol level in EL−/− mice is associated with increased phospholipid content in HDL particles, SR-BI−/− mice display markedly enlarged HDL particles shifted to larger subclasses with a phospholipid content similar to that of wild-type mice. Furthermore, absence of EL is associated with a 40% to 50% inhibition and absence of SR-BI, a ≈90% inhibition of endogenous lecithin cholesterol:acyltransferase rate. Conclusions— EL and SR-BI are major genetic determinants of HDL metabolism in vivo, each exercising independent and additive effects on HDL structure and function.

Endothelial lipase-modified high-density lipoprotein exhibits diminished ability to mediate SR-BI (scavenger receptor B type I)-dependent free-cholesterol efflux

Abstract: Endothelial lipase (EL) is a phospholipase with little triacylglycerol lipase activity. To assess structural and functional properties of EL-HDL (EL-modified high-density lipoprotein), HDL was incubated with conditioned medium from Cos-7 cells infected with adenovirus encoding human EL. After re-isolation of HDL by ultracentrifugation, TLC and HPLC analyses revealed that EL-HDL was markedly depleted in phosphatidylcholine and enriched in lyso-phosphatidylcholine compared with LacZ-HDL (control HDL) incubated with conditioned medium from Cos-7 cells infected with adenovirus encoding β-galactosidase. The EL-HDL was enriched in non-esterified fatty acids and, as revealed by lipid electrophoresis, was more negatively charged than control HDL. The HDL particle size as well as the total cholesterol, free cholesterol and triacylglycerol content of HDL were not significantly altered after EL modification. The ability of EL-HDL to mediate 3H-cholesterol efflux from SR-BI (scavenger receptor B type I) overexpressing Chinese-hamster ovary cells was impaired and markedly lower compared with LacZ-HDL at HDL concentrations of 100 μg/ml and above. Studies with 125I-labelled HDL showed almost unaltered binding affinity (Km values) and a slightly but significantly decreased binding capacity (Bmax values) of EL-HDL to SR-BI, compared with LacZ-HDL. The ATP-binding-cassette transporter A1-dependent cholesterol and phospholipid effluxes were not affected by EL modification. From these results, we concluded that EL modification alters chemical composition and physical properties of HDL, resulting in its decreased binding capacity to SR-BI and a diminished ability to mediate SR-BI-dependent cholesterol efflux.

Benzisothiazol-3-one-carboxylic acid amides as phospholipase inhibitors

Abstract: A novel class of benzisothiazole-3(2H)-one compounds is disclosed together with the use of such compounds for inhibiting hepatic lipase and/or endothelial lipase activity for treatment, amelioration or prevention of hepatic lipase and/or endothelial lipase mediated diseases. (I)

Structural basis of endothelial lipase tropism for HDL.

Abstract: SPECIFIC AIMSLipoprotein lipase (LPL) and endothelial lipase (EL), related members of the triglyceride lipase gene family, have distinct preferences for lipids along a spectrum of lipolytic activit

Endothelial lipase and cholesterol metabolism

Abstract: Endothelial lipase (EL), a new member of the lipase gene family, was recently cloned and has a significant role in plasma high-density lipoprotein levels (HDL). EL has a highly similar molecular homology to lipoprotein lipase and hepatic lipase. It is synthesized by endothelial cells and functions at the cell surface. EL primarily has phospholipase AI activity. Animals that overexpress EL showed decreased HDL cholesterol levels and those that lack EL show elevated levels of HDL cholesterol. The expression is highly regulated by cytokines and physical forces. These data suggest that EL may play a significant role in atherosclerosis.

Association of hepatic lipase and endothelial lipase polymorphisms with variation in nmr lipoprotein subclasses in caucasian, african-american and african-caribbean older men

Abstract: Despite higher prevalence of risk factors for coronary heart disease, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than Caucasians. In part, this is thought to be due to the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower levels of triglycerides and higher levels of HDL-C. The aim of the present study was to investigate the genetic contribution of two candidate genes, endothelial lipase (LIPG) and hepatic lipase (LIPC), to the ethnic variation in nuclear magnetic resonance (NMR) measured lipoproteins in 600 Caucasian, 100 African-American and 205 Tobago African-Caribbean men, older than 65 years. First, using a set of six ancestry informative markers, we estimated high African genetic contribution in the Tobago population (94%). A more favorable lipoprotein profile was observed in men of African origin compared to Caucasians. The frequency of the LIPG 584T allele in Tobago men (0.06) was five times less common than in Caucasians (0.29) and two times less common than in African-Americans (0.14). In African-Caribbeans, 584T allele was associated with lower small HDL and a greater HDL size, whereas in Caucasians and African-Americans, no significant association was found. Although, the LIPG 584T allele is protective in African-Caribbean men, its frequency is too low to explain the more favorable lipoprotein profile observed in these men. In contrast, the frequency of the LIPC -514T allele (0.57) was somewhat higher than the frequency in African-Americans (0.49), and three times as high as the frequency in Caucasians (0.20). 514C>T interacted with ethnicity to affect the levels of HDL-C, large HDL and HDL and LDL size. Carriers of 514T allele in both populations of African origin, but not in Caucasians, had elevated large HDL and greater HDL size. The higher frequency of the LIPC -514T allele in men of African origin significantly contributes to the more favorable distribution of HDL subclasses compared with Caucasians. Our findings have important public health relevance as they increase our understanding of Black-White differences in lipoprotein distributions, and are likely to increase our understanding of the underlying causes behind the ethnic differences in susceptibility to atherosclerosis.