Endothelial lipase and HDL metabolism

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.     

Endothelial lipase: a new member of the triglyceride lipase gene family

The triglyceride lipase gene family plays a central role in intestinal lipid absorption, energy homeostasis, lipoprotein metabolism, and atherosclerosis. A new member of this gene family, termed endothelial lipase, was recently reported. The presence of key functional motifs, the endothelial synthesis, the enzymatic profile, and the in-vivo metabolic effects of endothelial lipase suggest that, like other members of this gene family, endothelial lipase may play a role in energy delivery to tissues and in modulating lipoprotein metabolism, and could impact on atherogenesis.     

Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease

PURPOSE OF REVIEW: Adiponectin is secreted exclusively by adipocytes, aggregates in multimeric forms, and circulates at high concentrations in blood. This review summarizes recent studies highlighting cellular effects of adiponectin and its role in human lipid metabolism and atherosclerosis. RECENT FINDINGS: Adiponectin is an important autocrine/paracrine factor in adipose tissue that modulates differentiation of preadipocytes and favors formation of mature adipocytes. It also functions as an endocrine factor, influencing whole-body metabolism via effects on target organs. Adiponectin multimers exert differential biologic effects, with the high-molecular-weight multimer associated with favorable metabolic effects (i.e. greater insulin sensitivity, reduced visceral adipose mass, reduced plasma triglycerides, and increased HDL-cholesterol). Adiponectin influences plasma lipoprotein levels by altering the levels and activity of key enzymes (lipoprotein lipase and hepatic lipase) responsible for the catabolism of triglyceride-rich lipoproteins and HDL. It thus influences atherosclerosis by affecting the balance of atherogenic and antiatherogenic lipoproteins in plasma, and by modulating cellular processes involved in foam cell formation. SUMMARY: Recent studies emphasize the role played by adiponectin in the homeostasis of adipose tissue and in the pathogenesis of the metabolic syndrome, type 2 diabetes, and atherosclerosis. These pleiotropic effects make it an attractive therapeutic target for obesity-related conditions.     

In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity

Hepatic lipase (HL) is a key player in lipoprotein metabolism by modulating, through its lipolytic activity, the triglyceride (TG) and phospholipid content of apolipoprotein B (apoB)-containing lipoproteins and of high density lipoproteins (HDL), thereby affecting their size and density. A new and separate role has been suggested for HL in cellular lipoprotein metabolism, in which it serves as a ligand promoting cellular uptake of apoB-containing remnant lipoproteins and HDL. We tested the hypothesis that HL has both a lipolytic and a nonlipolytic role in human lipoprotein metabolism, by measuring lipid plasma concentrations, lipoprotein density distribution by density gradient ultracentrifugation, and lipoprotein composition, in three subjects with HL deficiency: two of the patients (S-1 and S-3) were characterized as having neither plasma HL activity nor detectable HL protein; the third subject (S-2) had no plasma HL activity but a detectable amount (35.5 ng/ml) of HL protein. All HL-deficient subjects showed a severalfold increase in lipoprotein TG content across the lipoprotein density spectrum [very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and HDL] as compared with control subjects. They also had remarkably more buoyant LDL particles (LDL-R(f) = 0.342;-0.394) as compared with the control subjects (LDL-R(f) = 0.303). Subjects S-1 and S-3 (no HL activity or protein) presented with a distinct increase in cholesterol and apoB levels in the IDL and VLDL density range as compared with patient S-2, with detectable HL protein, and the control subjects.This study provides evidence in humans that HL indeed plays an important role in lipoprotein metabolism independent of its enzymatic activity: in particular, inactive HL protein appears to affect VLDL and IDL particle concentration, whereas HL enzymatic activity seems to influence VLDL-, IDL-, LDL-, and HDL-TG content and their physical properties.     

Role of caveolin-1 in the regulation of lipoprotein metabolism

Lipoprotein metabolism plays an important role in the development of several human diseases, including coronary artery disease and the metabolic syndrome. A good comprehension of the factors that regulate the metabolism of the various lipoproteins is therefore key to better understanding the variables associated with the development of these diseases. Among the players identified are regulators such as caveolins and caveolae. Caveolae are small plasma membrane invaginations that are observed in terminally differentiated cells. Their most important protein marker, caveolin-1, has been shown to play a key role in the regulation of several cellular signaling pathways and in the regulation of plasma lipoprotein metabolism. In the present paper, we have examined the role of caveolin-1 in lipoprotein metabolism using caveolin-1-deficient (Cav-1(-/-)) mice. Our data show that, while Cav-1(-/-) mice show increased plasma triglyceride levels, they also display reduced hepatic very low-density lipoprotein (VLDL) secretion. Additionally, we also found that a caveolin-1 deficiency is associated with an increase in high-density lipoprotein (HDL), and these HDL particles are enriched in cholesteryl ester in Cav-1(-/-) mice when compared with HDL obtained from wild-type mice. Finally, our data suggest that a caveolin-1 deficiency prevents the transcytosis of LDL across endothelial cells, and therefore, that caveolin-1 may be implicated in the regulation of plasma LDL levels. Taken together, our studies suggest that caveolin-1 plays an important role in the regulation of lipoprotein metabolism by controlling their plasma levels as well as their lipid composition. Thus caveolin-1 may also play an important role in the development of atherosclerosis.     

Preheparin lipoprotein lipolytic activities: relationship to plasma lipoproteins and postheparin lipolytic activities.

To determine the putative metabolic relevance of preheparin versus postheparin lipoprotein lipases, the relationships of both pre- and postheparin lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) to plasma triglycerides, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol were determined in 93 men. Relationships of preheparin lipases to their respective postheparin lipases were also examined. Although relationships between the preheparin lipases and plasma triglycerides and HDL cholesterol were not apparent, both preheparin LPL (rs = 0.306, P = 0.0036) and HTGL (rs = 0.348, P = 0.0008) correlated with LDL cholesterol, a relationship not seen with either postheparin lipase. Both postheparin LPL (rs = 0.515, P = 0.0001) and postheparin HTGL (rs = -0.228, P = 0.0028), however, correlated with HDL cholesterol. In addition, postheparin LPL was inversely correlated with postheparin HTGL (rs = -0.363, P = 0.0003), whereas the relationship between preheparin LPL and preheparin HTGL was positive (rs = 0.228, P = 0.0009). Overall, these data point to differences between pre- and postheparin lipases in their relationships to lipoproteins, and one to another. The relationships of LDL cholesterol to both preheparin LPL and HTGL suggest that displacement of active forms of both lipases from their endothelial binding sites may mark triglyceride-rich lipoproteins or their remnants for metabolic pathways that lead to LDL.     

Modifications of plasma lipoproteins after lipase activation in patients with chylomicronemia

Lipoprotein lipase (LPL) and hepatic lipase (HL) are enzymatic activities involved in lipoprotein metabolism. The purpose of this study was to analyze the physicochemical modifications of plasma lipoproteins produced by LPL activation in two patients with apoC-II deficiency syndrome and by HL activation in two patients with LPL deficiency. LPL activation was achieved by the infusion of normal plasma containing apoC-II and HL was released by the injection of heparin. Lipoproteins were analyzed by ultracentrifugation in a zonal rotor under rate flotation conditions before and after lipase activation. The LPL activation resulted in: a reduction of plasma triglycerides; a reduction of fast-floating very low density lipoprotein (VLDL) concentration; an increase of intermediate density lipoprotein (IDL), which maintained unaltered flotation properties; an increase of low density lipoproteins (LDL) accompanied by modifications of their flotation rates and composition; no significant variations of high density lipoprotein (HDL) levels; and an increase of the HDL flotation rate. The HL activation resulted in: a slight reduction of plasma triglycerides; a reduction of the relative triglyceride content of slow-floating VLDL, IDL, LDL2, and HDL3 accompanied by an increase of phospholipid in VLDL and by an increase of cholesteryl ester in IDL; and a reduction of the HDL flotation rate. These experiments in chylomicronemic patients provide in vivo evidence that LPL and HL are responsible for plasma triglyceride hydrolysis of different lipoproteins, and that LPL is particularly involved in determining the levels and physicochemical properties of LDL. Moreover, in these patients, the LPL activation does not directly change the HDL levels, and LPL or HL does not produce a step-wise conversion of HDL3 to HDL2 (or vice versa) but rather modifies the flotation rates of all the HDL molecules present in plasma.     

The rabbit as an animal model of hepatic lipase deficiency

A natural deficiency of hepatic lipase in rabbits has been exploited to gain insights into the physiological role of this enzyme in the metabolism of plasma lipoproteins. A comparison of human and rabbit lipoproteins revealed obvious species differences in both low-density lipoproteins (LDL) and high-density lipoproteins (HDL), with the rabbit lipoproteins being relatively enlarged, enriched in triacylglycerol and depleted of cholesteryl ester. To test whether these differences related to the low level of hepatic lipase in rabbits, whole plasma or the total lipoprotein fraction from rabbits was either kept at 4 degrees C or incubated at 37 degrees C for 7 h in (i) the absence of lipase, (ii) the presence of hepatic lipase and (iii) the presence of lipoprotein lipase. Following incubation, the lipoproteins were recovered and subjected to gel permeation chromatography to determine the distribution of lipoprotein components across the entire lipoprotein spectrum. An aliquot of the lipoproteins was subjected also to gradient gel electrophoresis to determine the particle size distribution of the LDL and HDL. Both hepatic lipase and lipoprotein lipase hydrolysed lipoprotein triacylglycerol and to a much lesser extent, also phospholipid. There were, however, obvious differences between the enzymes in terms of substrate specificity. In incubations containing hepatic lipase, there was a preferential hydrolysis of HDL triacylglycerol and a lesser hydrolysis of VLDL triacylglycerol. By contrast, lipoprotein lipase acted primarily on VLDL triacylglycerol. When more enzyme was added, both lipases also acted on LDL triacylglycerol, but in no experiment did lipoprotein lipase hydrolyse the triacylglycerol in HDL. Coincident with the hepatic lipase-induced hydrolysis of LDL and HDL triacylglycerol, there were marked reductions in the particle size of both lipoprotein fractions, which were now comparable to those of human LDL and HDL3, respectively.     

Hepatic lipase: new insights from genetic and metabolic studies.

Hepatic lipase catalyses the hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Genetic deficiency of this enzyme is associated with a unique plasma lipoprotein profile, characterized by hypertriglyceridemia and elevated concentrations of intermediate density lipoproteins and HDL. Recent studies have identified common polymorphisms in the hepatic lipase gene that are associated with low hepatic lipase activity and increased concentrations of large HDL. Association studies using these polymorphisms are elucidating the effects of variation in hepatic lipase activity on plasma lipoprotein concentrations and susceptibility to coronary atherosclerosis.     

Hepatic lipase: a marker for cardiovascular disease risk and response to therapy

PURPOSE OF REVIEW: Hepatic lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether hepatic lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of hepatic lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on hepatic lipase proposed roles in lipoprotein metabolism. RECENT FINDINGS: Twenty to 30% of individual variation of hepatic lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the hepatic lipase gene (LIPC). This polymorphism, via its impact on hepatic lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low hepatic lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high hepatic lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. SUMMARY: Convincing evidence shows that hepatic lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of hepatic lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.     

Effects of heparin infusion on plasma lipoproteins in subjects with lipoprotein lipase deficiency: Evidence for a role of hepatic endothelial lipase in the metabolism of high-density lipoprotein subfractions in man

The role of heparin-releasable hepatic endothelial lipase (HL) in human plasma lipoprotein metabolism was investigated by examining the effects of intravenous infusion of heparin (180 units/kg over 2 h) in 8 subjects with primary extrahepatic lipoprotein lipase deficiency. In addition to reducing the triglyceride concentration in very low-density lipoproteins, heparin-induced release of HL reduced the phopholipid and protein concentrations in the HDL₂ subclass of high-density lipoprotein (by 28% and 36% respectively, mean values) and simultaneously increased the HDL₃ phospholipid concentration (by 23%), providing the first in vivo evidence for a function of HL in the interconversion of the major HDL subfractions in man.     

Recent studies of lipoprotein kinetics in the metabolic syndrome and related disorders

PURPOSE OF REVIEW: Dyslipoproteinemia is a cardinal feature of the metabolic syndrome that accelerates atherosclerosis. Recent in-vivo kinetic studies of dyslipidemia in the metabolic syndrome are reviewed here. RECENT FINDINGS: The dysregulation of lipoprotein metabolism may be caused by a combination of overproduction of VLDL apolipoprotein B-100, decreased catabolism of apolipoprotein B-containing particles, and increased catabolism of HDL apolipoprotein A-I particles. Nutritional modifications and increased physical exercise may favourably alter lipoprotein transport by collectively decreasing the hepatic secretion of VLDL apolipoprotein B and the catabolism of HDL apolipoprotein A-I, as well as by increasing the clearance of LDL apolipoprotein B. Conventional and new pharmacological treatments, such as statins, fibrates and cholesteryl ester transfer protein inhibitors, can also correct dyslipidemia by several mechanisms, including decreased secretion and increased catabolism of apolipoprotein B, as well as increased secretion and decreased catabolism of apolipoprotein A-I. SUMMARY: Kinetic studies provide a mechanistic insight into the dysregulation and therapy of lipid and lipoprotein disorders. Future research mandates the development of new tracer methodologies with practicable in-vivo protocols for investigating fatty acid turnover, macrophage reverse cholesterol transport, cholesterol transport in plasma, corporeal cholesterol balance, and the turnover of several subpopulations of HDL particles.     

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this “HDL hypothesis”. In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct.     

Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I.

The transport of HDL cholesteryl esters (CE) from plasma to the liver involves a direct uptake pathway, mediated by hepatic scavenger receptor B-I (SR-BI), and an indirect pathway, involving the exchange of HDL CE for triglycerides (TG) of TG-rich lipoproteins by cholesteryl ester transfer protein (CETP). We carried out HDL CE turnover studies in mice expressing human CETP and/or human lecithin:cholesterol acyltransferase (LCAT) transgenes on a background of human apoA-I expression. The fractional clearance of HDL CE by the liver was delayed by LCAT transgene, while the CETP transgene increased it. However, there was no incremental transfer of HDL CE radioactivity to the TG-rich lipoprotein fraction in mice expressing CETP, suggesting increased direct removal of HDL CE in the liver. To evaluate the possibility that this might be mediated by SR-BI, HDL isolated from plasma of the different groups of transgenic mice was incubated with SR-BI transfected or control CHO cells. HDL isolated from mice expressing CETP showed a 2- to 4-fold increase in SR-BI-mediated HDL CE uptake, compared to HDL from mice lacking CETP. The addition of pure CETP to HDL in cell culture did not lead to increased selective uptake of HDL CE by cells. However, when human HDL was enriched with TG by incubation with TG-rich lipoproteins in the presence of CETP, then treated with hepatic lipase, there was a significant enhancement of HDL CE uptake. Thus, the remodeling of human HDL by CETP, involving CE;-TG interchange, followed by the action of hepatic lipase (HL), leads to the enhanced uptake of HDL CE by cellular SR-BI.These observations suggest that in animals such as humans in which both the selective uptake and CETP pathways are active, the two pathways could operate in a synergistic fashion to enhance reverse cholesterol transport.     

Acute inhibition of hepatic lipase and increase in plasma lipoproteins after alcohol intake

Chronic alcohol intake is associated with an increase in fasting plasma high density lipoproteins (HDL). To study alcohol's acute effects on plasma lipoproteins, we measured plasma lipoprotein concentrations and activities of postheparin plasma lipases in nine normolipemic males after ingestion of 40 g of ethanol (as whiskey). After alcohol there was no change in lipoprotein lipase activity but hepatic lipase was decreased to 67% of baseline at 6 hr. There were associated increases in HDL phospholipids (12 mg/dl) and cholesterol (10 mg/dl) resulting in prominence of larger, lipid-enriched HDL particles. Changes were most pronounced in the HDL3 and HDL2a subclasses. Very low density lipoprotein (VLDL) phospholipids and cholesterol were also increased by 13 and 9 mg/dl, respectively, with no significant change in triglycerides. Changes in lipoproteins and lipase were largely reversed 10 hr after alcohol intake. The transient increases in VLDL and HDL lipids after alcohol may result in part from acute inhibition of hepatic lipase activity. The results suggest a role of hepatic lipase in the catabolism of phospholipids of VLDL and possibly HDL.     

Oral nicotine induces an atherogenic lipoprotein profile

Male squirrel monkeys were used to evaluate the effect of chronic oral nicotine intake on lipoprotein composition and metabolism. Eighteen yearling monkeys were divided into two groups: 1) Controls fed isocaloric liquid diet; and 2) Nicotine primates given liquid diet supplemented with nicotine at 6 mg/kg body wt/day. Animals were weighed biweekly, plasma lipid, glucose, and lipoprotein parameters were measured monthly, and detailed lipoprotein composition, along with postheparin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity, was assessed after 24 months of treatment. Although nicotine had no effect on plasma triglyceride or high density lipoproteins (HDL), the alkaloid caused a significant increase in plasma glucose, cholesterol, and low density lipoprotein (LDL) cholesterol plus protein while simultaneously reducing the HDL cholesterol/plasma cholesterol ratio and animal body weight. Levels of LDL precursors, very low density (VLDL) and intermediate density (IDL) lipoproteins, were also lower in nicotine-treated primates while total postheparin lipase (LPL + HTGL) activity was significantly elevated. Our data indicate that long-term consumption of oral nicotine induces an atherogenic lipoprotein profile (increases LDL, decreases HDL/total cholesterol ratio) by enhancing lipolytic conversion of VLDL to LDL. These results have important health implications for humans who use smokeless tobacco products or chew nicotine gum for prolonged periods.     

Long-chain polyunsaturated fatty acids, endothelial lipase and atherosclerosis

Endothelial lipase (EL), a new member of the lipase gene family, was recently cloned and has been shown to have a significant role in modulating the concentrations of plasma high-density lipoprotein levels (HDL). EL is closely related to lipoprotein and hepatic lipases both in structure and function. It is primarily synthesized by endothelial cells, functions at the cell surface, and shows phospholipase A1 activity. Overexpression of EL decreases HDL cholesterol levels whereas blocking its action increases concentrations of HDL cholesterol. Pro-inflammatory cytokines suppress plasma HDL cholesterol concentrations by enhancing the activity of EL. On the other hand, physical exercise and fish oil (a rich source of eicosapentaenoic acid and docosahexaenoic acid) suppress the activity of EL and this, in turn, enhances the plasma concentrations of HDL cholesterol. Thus, EL plays a critical role in the regulation of plasma HDL cholesterol concentrations and thus modulates the development and progression of atherosclerosis. The expression and actions of EL in specific endothelial cells determines the initiation and progression of atherosclerosis locally explaining the patchy nature of atheroma seen, especially, in coronary arteries. Both HDL cholesterol and EPA and DHA enhance endothelial nitric oxide (eNO) and prostacyclin (PGI2) synthesis, which are known to prevent atherosclerosis. On the other hand, pro-inflammatory cytokines augment free radical generation, which are known to inactivate eNO and PGI2. Thus, interactions between EL, pro- and anti-inflammatory cytokines, polyunsaturated fatty acids, and the ability of endothelial cells to generate NO and PGI2 and neutralize the actions of free radicals may play a critical role in atherosclerosis.     

Molecular basis of cholesterol homeostasis: lessons from Tangier disease and ABCA1

High-density lipoproteins (HDLs) play a role in transporting cholesterol from peripheral tissues to the liver for elimination from the body. Two hallmarks of cardiovascular disease are the presence of sterol-laden macrophages in the artery wall and reduced plasma HDL levels. A cell-membrane protein called ABCA1 mediates the secretion of excess cholesterol from cells into the HDL metabolic pathway. Mutations in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome characterized by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Because of its ability to deplete macrophages of cholesterol and to raise plasma HDL levels, ABCA1 has become a promising therapeutic target for preventing cardiovascular disease.     

Endothelial lipase is localized to follicular epithelial cells in the thyroid gland and is moderately expressed in adipocytes

Endothelial lipase (EL), a member of the triglyceride lipase gene family, has been shown to be a key player in HDL metabolism. Northern blots revealed that EL was highly expressed in endothelium, thyroid, lung, placenta, liver, and testis. In liver and adrenal gland, EL protein was localized with vascular endothelial cells but not parenchymal cells. EL was shown to be upregulated in tissues such as atherosclerotic plaque where it was located in macrophages, endothelial cells, and medial smooth muscle cells. The purpose of this study was to investigate the cellular localization of EL in thyroid and other tissues where EL is known to be expressed. Besides its presence in vascular endothelial and smooth muscle cells, EL protein was detected in the epithelial cells that line the follicles within the thyroid gland. EL-specific immunostaining was also found near the cell surface as well as in the cytoplasm of adipocytes. Using immunoblots, EL expression was confirmed in cultured human omental and subcutaneous adipocytes. EL expression, however, was not found in preadipocytes. These findings suggest that EL plays a role in thyroid and adipocyte biology in addition to its well-known role in endothelial function and HDL metabolism.     

Dynamic changes in mouse lipoproteins induced by transiently expressed human phospholipid transfer protein (PLTP): importance of PLTP in preβ-HDL generation

The plasma phospholipid transfer protein (PLTP) plays an important role in the regulation of plasma high density lipoprotein (HDL) levels and governs the distribution of HDL sub-populations. In the present study, adenovirus mediated overexpression of human PLTP in mice was employed to investigate the distribution of PLTP in serum and its effect on plasma lipoproteins. Gel filtration experiments showed that the distributions of PLTP activity and mass in serum are different, suggesting that human PLTP circulated in mouse plasma as two distinct forms, one with high and the other with low specific activity. Our study further demonstrates that overexpression of PLTP leads to depletion of HDL and that, as PLTP activity declines, replenishment of the HDL fraction occurs. During this process, the lipoprotein profile displays transient particle populations, including apoA-IV and apoE-rich particles in the LDL size range and small particles containing apoA-II only. The possible role of these particles in HDL reassembly is discussed. The increased PLTP activity enhanced the ability of mouse sera to produce preβ-HDL. The present results provide novel evidence that PLTP is an important regulator of HDL metabolism and plays a central role in the reverse cholesterol transport (RCT) process.