Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes

Recently, a murine scavenger receptor type B class I (SR-BI) was identified that binds high density lipoprotein (HDL) and mediates the selective uptake of cholesterol esters. The human CD36 and LIMPII analogous-1 (CLA-1) receptor shows high sequence homology with SR-BI, but their functional relationship has not been determined. Transfected cells expressing CLA-1 bound HDL with a Kd of about 35 microg/ml, similar to the Kd for HDL binding to rodent SR-BI. This binding resulted in an intracellular accumulation of HDL-derived [3H]cholesterol esters without internalization or degradation of 125I-apolipoprotein. CLA-1 was strongly expressed in the adrenal gland and was also abundant in liver and testis, suggesting that CLA-1, like SR-BI, could play a role in the metabolism of HDL. However, CLA-1 was also expressed in monocytes and, like SR-BI, recognized modified forms of low density lipoproteins as well as native LDL and anionic phospholipids. These findings suggest that CLA-1 might have additional physiological functions. We found that CLA-1 recognizes apoptotic thymocytes. Our results demonstrate that CLA-1, a close structural homologue of SR-BI, is also functionally related to SR-BI and may play an important role as a "docking receptor" for HDL in connection with selective uptake of cholesterol esters. An additional role in recognition of damaged cells is suggested by these studies.     

Expression of different lipoprotein receptors in natural killer cells and their effect on natural killer proliferative and cytotoxic activity

Natural killer (NK) cells take up chylomicrons (CM), very low density (VLDL), low density (LDL), high density (HDL) and acetyl-modified low density (AcLDL) lipoproteins through different receptors, VLDL being the lipoprotein with the highest uptake and HDL the lowest. The uptake of LDL can be selectively blocked by the anti-LDL receptor, which does not affect the uptake of CM, VLDL, HDL and AcLDL. Although the uptake of lipoproteins assessed by flow cytometry using DiI is not very high, the lipoproteins are able to induce an increase in proliferative responses, VLDL, AcLDL and HDL being the most important ones with 12- and 17-fold increments, respectively. CM, VLDL and LDL at low concentrations increase NK cytotoxic activity, while HDL and AcLDL inhibit, in a dose-dependent fashion, the killing of NK cells against K562. These results suggest the presence of four different receptors that are responsible for the cytotoxic and proliferative responses observed.     

Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL

Mouse and hamster SR-BI glycoproteins and their putative human counterpart CLA-I are so far the only scavenger receptors known to bind both native and modified lipoproteins. CD36, a multigland glycoprotein structurally related to SR-BI and CLA-1, has been reported to bind oxidized low density lipoprotein (OxLDL) and acetylated LDL (AcLDL). In this report, we have studied the ability of CD36 to bind native lipoproteins. By transient expression of human CD36 in mammalian and insect cells, we demonstrate that CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, VLDL, and, as previously reported, for OxLDL and AcLDL. The specificity of these interactions is supported by the dose-dependent inhibiton, effect of a monoclonal antibody against CD36. Furthermore, at least for HDL, binding to CD36 does not require the presence of apoE. These findings, together with preferential expression of CD36 in tissues performing very active fatty acid metabolism (skeletal muscle, heart, mammary epithelium, and adipose tissue) and its involvement in foam cell formation (macrophages), suggest that binding of lipoproteins to CD36 might contribute to the regulation of lipid metabolism, and to the pathogenesis of atherosclerosis.     

High density lipoprotein receptors, binding proteins, and ligands

Several HDL binding proteins, quite disparate in structure, have recently been cloned and their role in HDL metabolism is currently being assessed. High density lipoprotein binding protein, HBP (vigilin), which lacks a transmembrane domain is responsive to cell cholesterol levels, but its physiological significance remains unknown. On the other hand much is known about SR-B1, a member of the class B scavenger receptors. The level of SR-B1 expression correlates with both the selective transfer of cholesteryl ester into cells and cholesterol efflux from cells, the transfers probably mediated after docking of HDL at the cell surface. SR-B1 exhibits broad ligand specificity and, in animal models, appears to be regulated by the action of pituitary hormones that stimulate steroidogenesis, suggesting an important role for steroid hormone production in supplying precursor cholesterol. Another candidate HDL receptor, HB2, one of a pair of liver HDL binding proteins, shows high sequence homology with adhesion molecules, particularly activated leukocyte-cell adhesion molecule (ALCAM). When HB2 is overexpressed in cells, HDL binding increases. After PMA-induced differentiation of monocytes into macrophages, HB2 mRNA is strikingly elevated, which correlates with increased binding of HDL, but is down-regulated by cholesterol loading of macrophages. The ligand specificity of the HDL receptors, confounded by nonspecific lipid interactions, remains controversial. Their affinity for apoA-I versus apoA-I/A-II-rich HDL particles has clinical implications; both specific sequences in apoA-I and amphipathic alpha-helices may determine binding events. Post-receptor-mediated signalling events may regulate cell functions which, although not primarily related to lipid transport, nevertheless protect against coronary artery disease. Growing evidence for the involvement of lipid-poor apoA-I as a mediator of such pathways is also discussed.     

CLA-1 is an 85-kD plasma membrane glycoprotein that acts as a high-affinity receptor for both native (HDL, LDL, and VLDL) and modified (OxLDL and AcLDL) lipoproteins

Lipoprotein metabolism is regulated by the functional interplay between lipoprotein components and the receptors and enzymes with which they interact. Recent evidence indicates that the structurally related glycoproteins CD36 and SR-BI act as cell surface receptors for some lipoproteins. Thus, CD36 has been reported to bind oxidized LDL (OxLDL) and acetylated LDL (AcLDL), while SR-BI also binds native LDL and HDL. The cDNA of human CLA-1 predicts a protein 509 amino acids long that displays a 30% and an 80% amino acid identity with CD36 and mouse or hamster SR-BI, respectively. In this report, we describe the structural characterization of CLA-1 as an 85-kD plasma membrane protein enriched in N-linked carbohydrates. The expression of CLA-1 on mammalian and insect cells has been used to demonstrate that CLA-1 is a high-affinity specific receptor for the lipoproteins HDL, LDL, VLDL, OxLDL, and AcLDL. Northern blot analysis of the tissue distribution of CLA-1 in humans indicated that its expression is mostly restricted to tissues performing very active cholesterol metabolism (liver and steroidogenic tissues). This finding, in the context of the capability of this receptor to bind to both native and modified lipoproteins, strongly suggests that the CLA-1 receptor contributes to lipid metabolism and atherogenesis.     

In vitro proliferation and adhesion of basic fibroblast growth factor-producing fibroblasts on platinum coils

The rate of the non-directional transfer of cholesteryl ester and triglyceride by human cholesteryl ester transfer protein (CETP) was measured between human plasma lipoproteins by monitoring fluorescence spectrum of pyrene-labeled lipid. The transfer rates between high density lipoproteins (HDLs) and between low density lipoproteins (LDLs) were both directly proportional to the substrate lipid concentration within the physiological range of the lipoprotein concentration. Higher preference of cholesteryl ester transfer to triglyceride was demonstrated with HDL than LDL. Although the highly selective binding of CETP to HDL was observed in the electrophoretic analysis, the transfer rate was only moderately higher with HDL for cholesteryl ester and not so at all for triglyceride. In addition, the rate of cholesteryl ester transfer between LDLs was uninfluenced by the presence of a small amount of HDL that is just sufficient to absorb all the CETP in the reaction mixture. The results indicated the preferential transfer of cholesteryl ester over triglyceride by CETP in the interaction with HDL in non-directional lipid transfer reaction among lipoproteins. However, the apparent binding of CETP to HDL does not seem to play an essential role in this type of lipid transfer by CETP.     

Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol

Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50-70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may influence the development of coronary artery disease.     

Diet, plasma lipoproteins and experimental atherosclerosis in baboons (Papio sp.)

Diet-induced hyperlipidaemia in baboons is similar to that in humans. As in humans, the ratio between low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol is a major determinant of atherosclerosis. Baboons, like humans and other non-human primates, vary in their lipaemic responses to dietary lipids. By selective breeding based on variability in plasma and lipoprotein cholesterol response to diet, lines of baboons with high and low responses of various lipoproteins have been developed. Genetic analyses suggest that lipoprotein patterns in response to dietary cholesterol and fat are heritable. Metabolic and molecular studies of high and low LDL and HDL cholesterol responses to dietary lipids have suggested that different mechanisms regulate plasma LDL cholesterol on the chow and on the high cholesterol-high fat (HCHF) diet. On the chow diet, plasma LDL cholesterol levels are positively associated with cholesterol absorption and negatively associated with hepatic LDL receptor levels and, thus, cholesterol absorption and LDL receptors seem to regulate plasma LDL cholesterol levels. However, when the animals consume a human-like fat- and cholesterol-enriched diet, plasma LDL cholesterol levels are not associated with either cholesterol absorption or hepatic LDL receptor mRNA levels, but are negatively associated with plasma 27-hydroxycholesterol concentrations, hepatic sterol 27-hydroxylase activity, and mRNA levels. Hepatic sterol 27-hydroxylase activity and mRNA levels are induced by dietary cholesterol and fat in low responding baboons more than in high responding baboons. Thus, the ability to induce sterol 27-hydroxylase determines the LDL cholesterol response in baboons. High HDL response baboons often have high levels of HDL1 in their plasma. Our studies suggest that the N-terminal fragment of apo C-I with 38 amino acids and a molecular weight of approximately 4 kDa acts as a cholesteryl ester transfer inhibitor peptide in high HDL1 baboons. The inhibitor peptide associates with apo A-1 in HDL to produce a modified apo A-1 protein with a molecular weight of approximately 31 kDa. The inhibitor peptide is a gene product and the presence of this peptide produces an antiatherogenic high HDL1 phenotype.     

Lipids and atherosclerosis

Atherosclerosis is a degenerative pathology of blood vessels leading to coronary heart disease, myocardial infarction and stroke. The basic lesion of atherosclerosis is the fibrous plaque, which consists of lipids, smooth muscle cells, macrophages and connective tissue matrix. Data derived from experimental and clinical studies indicate the crucial role of elevated serum LDL-cholesterol concentration in the formation of atherosclerotic lesions. HDL removes cholesterol from the arterial wall, stimulates arterial prostacyclin synthesis, inhibits adhesion molecules expression, has antioxidant properties and protects against atherosclerosis. Lipoprotein (a) competes with plasminogen for its binding site, leading to reduced fibrinolysis and is an important link between thrombogenesis and atherosclerosis. The pathogenic role of lipids in atherogenesis is discussed.     

Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands

The LDL receptor family members are endocytic receptors composed of repeated protein modules, including clusters of ligand binding LDL receptor class A (LA) repeats. The large (approximately 600 kDa) members LRP and megalin bind numerous structurally unrelated and often complex ligands at different combinations of sites. LRP is expressed in a wide but restricted set of cell types including hepatocytes, macrophages, smooth muscle cells, and neurons of the CNS. Megalin is expressed in various epithelia including proximal kidney tubules, intestine, and ependymal cells. The two receptors share a multitude of ligands, and their function in vivo is therefore to a large extent determined by their expression pattern. For example, both receptors can endocytose lipoproteins, but this function appears mainly relevant for LRP. In addition, LRP helps regulating urokinase receptor expression on the cell surface via ligand-mediated internalization followed by return of the naked urokinase receptor to the cell surface. Both receptors also have specialist functions. LRP is specific for binding of alpha2-macroglobulin-proteinase complexes and provides clearance of the complexes and of peptides, e.g. cytokines, associated with the complex. Megalin has important functions in vitamin B12 homeostasis since it specifically mediates uptake of the vitamin B12-transcobalamin complex and helps building a storage pool for the vitamin in the kidneys. Moreover, megalin binds cubilin, the recently identified receptor for B12-intrinsic factor complex, thus providing a mechanism for uptake of dietary vitamin B12. Finally, megalin specifically mediates uptake of apolipoprotein J/clusterin, a binding protein for the Abeta peptide implicated in Alzheimer's disease. The binding of multiple complex ligands that belong to distinct physiological systems provides a challenge in future studies aiming at elucidating the role of LRP and megalin in disease mechanisms.     

Ultrafast contrast-enhanced three-dimensional MR angiography: state of the art

Selective uptake of high-density lipoprotein- (HDL-) associated cholesteryl esters (CE), i.e. lipid uptake independent from particle uptake, delivers CE to the liver and steroidogenic tissues in vivo. In vitro, besides hepatocytes and steroidogenic cells many other cell types selectively take up HDL CE. Hepatic lipase (HL) stimulates the internalisation of apoprotein (apo) B-containing lipoproteins by hepatocytes independent from lipolysis. In this study the role of HL in the hepatic metabolism of apo A-I-containing lipoproteins, i.e. HDL, was investigated. HDL3 (d = 1.125-1.21 g/ml) was radiolabeled in its protein (125I) and in its CE moiety ([3H]cholesteryl oleyl ether, ([3H]CEt)). HL originated from tissue culture media of hepatoma cells and from post-heparin plasma. Human Hep 3B hepatoma cells incubated in medium containing radiolabeled HDL3. In the absence of HL, the rate of apparent HDL3 particle uptake according to the lipid tracer ([3H]CEt) was in most cases in approximately 10-fold excess on that due to the protein label (125I), indicating selective CE uptake from HDL3. Addition of HL to these incubations increased the cellular uptake of [3H]CEt and of 125I from HDL3 and quantitatively the most prominent effect was an up to approximately 2.5-fold stimulation of apparent selective CE uptake ([3H]CEt-125I). This increase in selective CE uptake was observed in the presence of tetrahydrolipstatin, an inhibitor of the catalytically active site of HL, suggesting that this HL effect is independent from lipolysis. HL binds to cell surface heparan sulfate proteoglycans. To explore the role of these molecules for the HL effect on selective CE uptake, hepatoma cells were depleted of proteoglycans or Chinese hamster ovary (CHO) cells deficient in proteoglycan synthesis were used. Proteoglycan-deficiency reduced the HL-mediated increase in selective uptake by more than 80%. To investigate if low-density lipoprotein (LDL) receptors or the LDL receptor-related protein (LRP) are involved in the HL effect on selective CE uptake, murine embryonic fibroblasts (MEF) were used which are deficient in these receptors; alternatively, monensin, an inhibitor of endocytosis was present in the medium of Hep 3B cells during the uptake assay for labeled HDL3. These experiments yielded no evidence for a role of LDL receptors or LRP in the HL-mediated increase in selective CE uptake. In summary, HL mediates an increase in HDL3 selective CE uptake by human Hep 3B hepatoma cells. This HL effect is independent from lipolysis and independent from LRP and LDL receptors. However this HL effect is susceptible to cell surface proteoglycan deficiency. The potential physiologic implication is that HL modifies HDL selective CE uptake by the liver in vivo and such an effect could play a role in reverse cholesterol transport.     

Interaction of apolipoprotein AII with the putative high-density lipoprotein receptor

There is strong evidence to indicate that binding of HDL by cells is due to recognition of apoproteins residing on the surface of the lipoprotein by the putative HDL receptor(s). Although both of the major HDL apoproteins, AI and AII, are recognized by the putative receptor, the nature of the binding interaction and the domains of the apoproteins involved are largely unknown. Previous data from this laboratory led to the proposal of a model to explain how HDL particles containing AII interacted with the HDL receptor in a different manner as compared to HDL particles which contain apoAI but not apoAII [Vadiveloo, P. K., & Fidge, N. H. (1992) Biochem. J. 284, 145-151]. The model predicted that each chain of the apoAII homodimer contained a binding domain capable of interacting with the HDL receptor. This model was tested in the current study by preparing apoAII monomers, complexing them with phospholipid, and determining the ability of these complexes to bind to putative HDL receptors in rat liver plasma membranes (RLPM) and bovine aortic endothelial cell membranes (BAECM) by ligand blotting. The data showed that these complexes were bound by HB1 and HB2 from RLPM, and to the 110-kDa HDL binding protein from BAECM, providing critical evidence to support the model. Further investigation into the binding interaction revealed that apoAII complexed with phospholipid (apoAII-PC) bound more than delipidated apoAII, which bound more than delipidated apoAII monomers. Thus, optimum binding required the presence of lipid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neutral lipid mass transfer among lipoproteins in plasma from normolipidemic subjects is not an equimolar heteroexchange

To further characterize the cholesteryl ester transfer protein (CETP)-mediated distribution of neutral lipids that occurs among lipoproteins in plasma, the net mass transfer of core lipids between donor and acceptor lipoproteins in intact plasma was measured in ten healthy normolipidemic subjects. The rate of loss of cholesteryl ester (CE) from high density lipoprotein-3 (HDL3) (19.5 +/- 8.8 nmol/ml per h) was linear and increased significantly (P < 0.01) during the 6-h incubation. Approximately 50% of the CE transferred from HDL3 (118.7 +/- 54.3 nmol/ml) went to very low density lipoprotein (VLDL); the remainder was distributed to low density lipoprotein (LDL) (approximately 30%) and HDL2 (approximately 20%). The rate of loss of triglyceride (TG) from VLDL (14.5 +/- 6.6 nmol/ml per h) to the HDL subfractions and LDL also was linear and increased significantly with time (P < 0.01). About 50% of the TG mass lost from VLDL (85.2 +/- 38.4 nmol/ml) was transferred to LDL and the remainder was recovered in HDL2 (approximately 10%) and HDL3 (approximately 40%). As the number of nmoles of CE lost from HDL3 was almost three times greater than the nmoles of TG it acquired, these findings indicate that the exchange of core lipids in plasma that result from the interaction between CETP-VLDL-HDL3 is not equimolar. Even in the absence of VLDL, HDL3 continued to donate CE to LDL and HDL2 to almost the same degree as in intact plasma (plasma minus VLDL: 17.5 +/- 5.9 nmol/ml per h vs. intact plasma: 20.2 +/- 7.5 nmol/ml per h) without accepting any TG. Our findings demonstrate that independent pathways exist for the transfer of CE and TG among the plasma lipoproteins and, contrary to what is generally believed, a heteroexchange of TG for CE during cholesteryl ester transfer is not obligatory.     

Cholesterol ester transfer protein: a molecule with three faces?

The pathogenesis of atherosclerosis continues to be a focus of intensive study. One of the more recent players in the atherosclerosis drama is cholesterol ester transfer protein (CETP). CETP is primarily involved in lipid transfer between lipoproteins, for example, from high-density lipoproteins (HDL) to apo B-containing lipoproteins, but CETP has also been found to take up cholesterol directly from cells without the co-participation of lipoproteins, and it is still not clear whether CETP should be classified as a beneficial or as a harmful protein. Some of the important evidence for these conflicting theories is examined here, with special reference to situations where CETP appears to be proatherogenic, instances where CETP seems to assume an antiatherogenic role, and situations where CETP seems to be both proatherogenic and antiatherogenic. In addition, the metabolic context of CETP and the modification of CETP substrates play crucial roles that are not always recognized when judgements about the role of CETP in atherosclerosis are recorded.     

Uptake and metabolism of lipoproteins from patients with diabetes mellitus type II by glomerular epithelial cells

BACKGROUND: Recent studies suggest that dyslipidaemia accelerates the progression of diabetic nephropathy, but the various pathomechanisms underlying such abnormalities are not completely delineated. METHODS: We isolated, radiolabelled, and characterized very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from eight diabetic patients with moderate impairment of renal function and dyslipidaemia and studied their interaction with LDL receptors in human glomerular epithelial cells. RESULTS: While diabetic VLDL showed no compositional changes, LDL particles contained a higher proportion of triglycerides at the expense of cholesterol in comparison with healthy controls. Despite differences in composition, both VLDL and LDL from patients exhibited reduced receptor affinity and cellular uptake capacity by glomerular epithelial cells. Since LDL composition was altered intracellular cholesterol homeostasis was investigated. Due to reduced cholesterol content and lower uptake capacity, diabetic LDL were less effective in suppressing intracellular sterol synthesis and in activating acylcholesterol acyltransferase than LDL from controls. Electrophoretic mobility of apoB from diabetic patients was enhanced as compared to controls, most probably due to the higher degree of glycation (17 + 1.7 versus 11 + 1%, P < 0.05) but not to oxidation (TBARS 0.5 + 0.2 versus 0.2 + 0.1 mumol/1). Oxidized LDL was not taken up in significant amounts, indicating no scavenger receptor activity in glomerular epithelial cells. CONCLUSION: The receptor-specific uptake of diabetic VLDL and LDL by glomerular epithelial cells is impaired. Compositional changes of the LDL particle and glycation of the protein moiety may contribute to altered glomerular uptake. However, glycation of the protein moiety may be superior to compositional changes. Because glomerular structures like mesangial matrix and endothelial cells are known for preferential binding of modified lipoproteins, further studies are required to elucidate their potential role in the progression of diabetic glomerulosclerosis.     

Effects of insulin deficiency on lipoproteins and their hepatic receptors in Rico rats

The present study was designed to examine the effect of streptozotocin (STZ)-induced diabetes on the plasma lipoprotein profile and hepatic expression of the LDL receptor and HDL binding protein (HB2) in hypercholesterolemic Rico rats. The plasma level of HDL1 (density range 1.040-1.063), which is particularly high in this rat strain, decreased (-25%) 28 d after STZ administration (50 mg/kg). In contrast, the treatment increased (+54%) the plasma concentration of HDL2 (density range 1.063-1.210). These variations in the lipoprotein concentrations were associated with inverse changes in the hepatic protein levels of the LDL receptor (+118%) and HB2 (-46%). These results suggest that the hepatic expression of HB2, a putative HDL receptor, can influence the plasma level of apo Al-rich HDL as has already been shown for the LDL receptor for apo B/E containing lipoproteins.     

Novel large apolipoprotein E-containing lipoproteins of density 1.006-1.060 g/ml in human cerebrospinal fluid

Although the critical role of apolipoprotein E (apoE) allelic variation in Alzheimer's disease and in the outcome of CNS injury is now recognized, the functions of apoE in the CNS remain obscure, particularly with regard to lipid metabolism. We used density gradient ultracentrifugation to identify apoE-containing lipoproteins in human CSF. CSF apoE lipoproteins, previously identified only in the 1.063-1.21 g/ml density range, were also demonstrated in the 1.006-1.060 g/ml density range. Plasma lipoproteins in this density range include low-density lipoprotein and high-density lipoprotein (HDL) subfraction 1 (HDL1). The novel CSF apoE lipoproteins are designated HDL1. No immunoreactive apolipoprotein A-I (apo A-I) or B could be identified in the CSF HDL1 fractions. Large lipoproteins 18.3 +/- 6.6 nm in diameter (mean +/- SD) in the HDL1 density range were demonstrated by electron microscopy. Following fast protein liquid chromatography of CSF at physiologic ionic strength, apoE was demonstrated in particles of average size greater than particles containing apoA-I. The largest lipoproteins separated by this technique contained apoE without apoA-I. Thus, the presence of large apoE-containing lipoproteins was confirmed without ultracentrifugation. Interconversion between the more abundant smaller apoE-HDL subfractions 2 and 3 and the novel larger apoE-HDL1 is postulated to mediate a role in cholesterol redistribution in brain.     

Hepatic lipase affects both HDL and ApoB-containing lipoprotein levels in the mouse

Transgenic mice were created overproducing a range of human HL (hHL) activities (4-23-fold increase) to further examine the role of hepatic lipase (HL) in lipoprotein metabolism. A 5-fold increase in heparin releasable HL activity was accompanied by moderate (approx. 20%) decreases in plasma total and high density lipoprotein (HDL) cholesterol and phospholipid (PL) but no significant change in triglyceride (TG). A 23-fold increase in HL activity caused a more significant decrease in plasma total and HDL cholesterol, PL and TG (77%, 64%, 60%, and 24% respectively), and a substantial decrease in lipoprotein lipids amongst IDL, LDL and HDL fractions. High levels of HL activity diminished the plasma concentration of apoA-I, A-II and apoE (76%, 48% and 75%, respectively). In contrast, the levels of apoA-IV-containing lipoproteins appear relatively resistant to increased titers of hHL activity. Increased hHL activity was associated with a progressive decrease in the levels and an increase in the density of LpAI and LpB48 particles. The increased rate of disappearance of 125I-labeled human HDL from the plasma of hHL transgenic mice suggests increased clearance of HDL apoproteins in the transgenic mice. The effect of increased HL activity on apoB100-containing lipoproteins was more complex. HL-deficient mice have substantially decreased apoB100-containing low density lipoproteins (LDL) compared to controls. Increased HL activity is associated with a transformation of the lipoprotein density profile from predominantly buoyant (VLDL/IDL) lipoproteins to more dense (LDL) fractions. Increased HL activity from moderate (4-fold) to higher (5-fold) levels decreased the levels of apoB100-containing particles. Thus, at normal to moderately high levels in the mouse, HL promotes the metabolism of both HDL and apoB-containing lipoproteins and thereby acts as a key determinant of plasma levels of both HDL and LDL.