Role Of Hepatic Lipase Research Articles

Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.

Secretion of triacylglycerol-poor VLDL particles from McA-RH7777 cells expressing human hepatic lipase

Hepatic lipase (HL) plays a role in the catabolism of apolipoprotein (apo)B-containing lipoproteins through its lipolytic and ligand-binding properties. We describe a potential intracellular role of HL in the assembly and secretion of VLDL. Transient or stable expression of HL in McA-RH7777 cells resulted in decreased (by 40%) incorporation of [(3)H]glycerol into cell-associated and secreted triacylglycerol (TAG) relative to control cells. However, incorporation of [(35)S]methionine/cysteine into cell and medium apoB-100 was not decreased by HL expression. The decreased (3)H-TAG synthesis/secretion in HL expressing cells was not attributable to decreased expression of genes involved in lipogenesis. Fractionation of medium revealed that the decreased [(3)H]TAG from HL expressing cells was mainly attributable to decreased VLDL. Expression of catalytically-inactive HL (HL(SG)) (Ser-145 at the catalytic site was substituted with Gly) in the cells also resulted in decreased secretion of VLDL-[(3)H]TAG. Examination of lumenal contents of microsomes showed a 40% decrease in [(3)H]TAG associated with lumenal lipid droplets in HL or HL(SG) expressing cells as compared with control. The microsomal membrane-associated [(3)H]TAG was decreased by 50% in HL expressing cells but not in HL(SG) expressing cells. Thus, expression of HL, irrespective of its lipolytic function, impairs formation of VLDL precursor [(3)H]TAG in the form of lumenal lipid droplets. These results suggest that HL expression in McA-RH7777 cells result in secretion of [(3)H]TAG-poor VLDL.

Phospholipid transfer protein deficiency ameliorates diet-induced hypercholesterolemia and inflammation in mice

Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids from triglyceride-rich lipoproteins into HDL. PLTP has been shown to be an important factor in lipoprotein metabolism and atherogenesis. Here, we report that chronic high-fat, high-cholesterol diet feeding markedly increased plasma cholesterol levels in C57BL/6 mice. PLTP deficiency attenuated diet-induced hypercholesterolemia by dramatically reducing apolipoprotein E-rich lipoproteins (-88%) and, to a lesser extent, LDL (-40%) and HDL (-35%). Increased biliary cholesterol secretion, indicated by increased hepatic ABCG5/ABCG8 gene expression, and decreased intestinal cholesterol absorption may contribute to the lower plasma cholesterol in PLTP-deficient mice. The expression of proinflammatory genes (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) is reduced in aorta of PLTP knockout mice compared with wild-type mice fed either a chow or a high-cholesterol diet. Furthermore, plasma interleukin-6 levels are significantly lower in PLTP-deficient mice, indicating reduced systemic inflammation. These data suggest that PLTP appears to play a proatherogenic role in diet-induced hyperlipidemic mice.

Combined hyperlipidemia/hyperalphalipoproteinemia associated with premature spontaneous atherosclerosis in mice lacking hepatic lipase and low density lipoprotein receptor

Background and methods Hepatic lipase (HL) is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of triglyceride-rich lipoprotein remnants and high density lipoproteins. The search described here concentrated on the description of the double invalidation of the HL and LDL receptor genes in mice in order to better understand the possible role of HL in combined hyperlipidemia/hyperalphalipoproteinemia and development of atherosclerosis. Results We show here that mice lacking both endogenous HL and LDL receptor (HL−/−:LDLR−/−) dramatically increased their plasma triglyceride-rich lipoproteins and their remnants as a consequence of reduced liver uptake. This result is strenghthened by the fact that HL−/−:LDLR−/− were found to overexpress LRP, LSR, and apoE genes. Interestingly, HL−/−:LDLR−/− mice showed premature spontaneous atherosclerosis and aortic lesions from 1-year-old animals were two-fold larger than those of LDLR−/− single mutants. We confirmed that HL−/− and wild-type mice did not develop atherosclerosis lesion even 1 year after birth. Conclusions Analysis of this double HL–LDLR knockout mouse model provides in vivo evidence that HL has a major role in the clearance of TRL remnants when LDLR is deficient and in the reduction of the development of atherosclerosis.

Attenuated corticosterone response to chronic ACTH stimulation in hepatic lipase-deficient mice: evidence for a role for hepatic lipase in adrenal physiology

Hepatic lipase (HL), a liver-expressed lipolytic enzyme, hydrolyzes triglycerides and phospholipids in lipoproteins and promotes cholesterol delivery through receptor-mediated whole particle and selective cholesterol uptake. HL activity also occurs in the adrenal glands, which utilize lipoprotein cholesterol to synthesize glucocorticoids in response to pituitary ACTH. It is likely that the role of adrenal HL is to facilitate delivery of exogenous cholesterol for glucocorticoid synthesis. On this basis, we hypothesized that HL deficiency would blunt the glucocorticoid response to ACTH. Furthermore, because exogenous cholesterol also is derived from the LDL receptor (LDLR) pathway, we hypothesized that LDLR deficiency would blunt the response to ACTH. To test these hypotheses, we compared the corticosterone response to eight daily ACTH injections in HL-deficient (hl-/-), LDLR-deficient (Ldlr-/-), and HL- and LDLR-doubly deficient (Ldlr-/- hl-/-) mice with that in wild-type (WT) mice. Plasma corticosterone levels were measured on days 2, 5, and 8. Differences in plasma corticosterone levels between genotypes were analyzed by Kruskal-Wallis one-way ANOVA on ranks and pairwise multiple comparisons by Dunn's test. Our results demonstrate a trend toward reductions in plasma corticosterone levels on day 2 and significant reductions on day 5 and day 8 in the knockout models. Thus, on day 5, plasma corticosterone levels were reduced by 57, 70, and 73% (all P < 0.05) and on day 8 by 76, 59, and 63% (all P < 0.05) in hl-/-, Ldlr-/-, and Ldlr-/- hl-/- mice, respectively. These results demonstrate that HL deficiency, like LDLR deficiency, blunts the adrenal response to chronic ACTH stimulation and suggest a novel role for HL in adrenal physiology.

Evidence that endothelial lipase remodels high density lipoproteins without mediating the dissociation of apolipoprotein A-I

Endothelial lipase (EL) is a triglyceride lipase gene family member that has high phospholipase and low triglyceride lipase activity. The aim of this study was to determine whether the phospholipase activity of EL is sufficient to remodel HDLs into small particles and mediate the dissociation of apolipoprotein A-I (apoA-I). Spherical, reconstituted HDLs (rHDLs) containing apoA-I only [(A-I)rHDLs], apoA-II only [(A-II)rHDLs], or both apoA-I and apoA-II [(A-I/A-II) rHDLs] were prepared. The rHDLs, which contained only cholesteryl esters in their core and POPC on the surface, were incubated with EL. As the rHDLs did not contain triacylglycerol, only the POPC was hydrolyzed. Hydrolysis was greater in the (A-I/A-II)rHDLs than in the (A-I)rHDLs. The (A-II)rHDL phospholipids were not hydrolyzed by EL. EL remodeled the (A-I)rHDLs and (A-I/A-II)rHDLs, but not the (A-II)rHDLs, into smaller particles. The reduction in particle size was related to the amount of phospholipid hydrolysis, with the diameter of the (A-I/A-II)rHDLs decreasing more than that of the (A-I)rHDLs. These changes did not affect the conformation of apoA-I, and neither apoA-I nor apoA-II dissociated from the rHDLs. Comparable results were obtained when human plasma HDLs were incubated with EL. These results establish that the phospholipase activity of EL remodels plasma HDLs and rHDLs into smaller particles without mediating the dissociation of apolipoproteins.

Sensitive assay for hormone-sensitive lipase using NBD-labeled monoacylglycerol to detect low activities in rat adipocytes

The recent finding that p-nitrobenzofurazan (NBD)-FA is incorporated into and released from the acylglycerols of isolated rat adipocytes in an insulin-sensitive manner [G. Muller, H. Jordan, C. Jung, H. Kleine, and S. Petry. 2003. Biochimie. 85: 1245-1246] suggests that NBD-FA-labeled acylglycerols are cleaved by rat adipocyte hormone-sensitive lipase (HSL) in vivo. In the present study, we developed a continuous, sensitive in vitro lipase assay using a monoacylglycerol (MAG) containing NBD (NBD-MAG). NBD-MAG was found to provide an efficient substrate for rat adipocyte and human recombinant HSL. Ultrasonic treatment applied in the presence of phospholipids leads to the incorporation of NBD-MAG into the phospholipid liposomes and to a concomitant change of its spectrophotometric properties. The enzymatic release of NBD-FA and its dissociation from the carrier liposomes is accompanied by the recovery of the original spectrophotometric characteristics. The rate of lipolysis was monitored by measuring the increase in optical density at 481 nm, which was found to be linear with time and linearly proportional to the amount of lipase added. To assess the specific activity of recombinant HSL, we determined the molar extinction coefficient of NBD-FA under the assay conditions. This convenient assay procedure based on NBD-MAG should facilitate the search for small molecule HSL inhibitors.

Hepatic lipase, lipoprotein metabolism, and atherogenesis.

The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis.

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice.

Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO x HL-KO mice, as well as LCAT-Tg and LCAT-Tg x HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo.

Characterization of the lipolytic activity of endothelial lipase

Endothelial lipase (EL) is a new member of the triglyceride lipase gene family previously reported to have phospholipase activity. Using radiolabeled lipid substrates, we characterized the lipolytic activity of this enzyme in comparison to lipoprotein lipase (LPL) and hepatic lipase (HL) using conditioned medium from cells infected with recombinant adenoviruses encoding each of the enzymes. In the absence of serum, EL had clearly detectable triglyceride lipase activity. Both the triglyceride lipase and phospholipase activities of EL were inhibited in a dose-dependent fashion by the addition of serum. The ratio of triglyceride lipase to phospholipase activity of EL was 0.65, compared with ratios of 24.1 for HL and 139.9 for LPL, placing EL at the opposite end of the lipolytic spectrum from LPL. Neither lipase activity of EL was influenced by the addition of apolipoprotein C-II (apoC-II), indicating that EL, like HL, does not require apoC-II for activation. Like LPL but not HL, both lipase activities of EL were inhibited by 1 M NaCl. The relative ability of EL, versus HL and LPL, to hydrolyze lipids in isolated lipoprotein fractions was also examined using generation of FFAs as an end point. As expected, based on the relative triglyceride lipase activities of the three enzymes, the triglyceride-rich lipoproteins, chylomicrons, VLDL, and IDL, were efficiently hydrolyzed by LPL and HL. EL hydrolyzed HDL more efficiently than the other lipoprotein fractions, and LDL was a poor substrate for all of the enzymes.

The role of hepatic lipase in lipoprotein metabolism

Hepatic lipase (HL) is one of two major lipases released from the vascular bed by intravenous injection of heparin. HL hydrolyzes phospholipids and triglycerides of plasma lipoproteins and is a member of a lipase superfamily that includes lipoprotein lipase and pancreatic lipase. The enzyme can be divided into an NH2-terminal domain containing the catalytic site joined by a short spanning region to a smaller COOH-terminal domain. The NH2-terminal portion contains an active site serine in a pentapeptide consensus sequence, Gly–Xaa–Ser–Xaa–Gly, as part of a classic Ser–Asp–His catalytic triad, and a putative hinged loop structure covering the active site. The COOH-terminal domain contains a putative lipoprotein-binding site. The heparin-binding sites may be distributed throughout the molecule, with the characteristic elution pattern from heparin–sepharose determined by the COOH-terminal domain. Of the three N-linked glycosylation sites, Asn-56 is required for efficient secretion and enzymatic activity. HL is hypothesized to directly couple HDL lipid metabolism to tissue/cellular lipid metabolism. The potential significance of the HL pathway is that it provides the hepatocyte with a mechanism for the uptake of a subset of phospholipids enriched in unsaturated fatty acids and may allow the uptake of cholesteryl ester, free cholesterol and phospholipid without catabolism of HDL apolipoproteins. HL can hydrolyze triglyceride and phospholipid in all lipoproteins, but is predominant in the conversion of intermediate density lipoproteins to LDL and the conversion of post-prandial triglyceride-rich HDL into the post-absorptive triglyceride-poor HDL. It has been suggested that enzymatically inactive HL can play a role in hepatic lipoprotein uptake forming a ‘bridge’ by binding to the lipoprotein and to the cell surface. This raises the interesting possibility that production and secretion of mutant inactive HL could promote clearance of VLDL remnants. We have described a rare family with HL deficiency. Affected patients are compound heterozygotes for a mutation of Ser267Phe that causes an inactive enzyme and a mutation of Thr383Met that results in impaired secretion of HL and reduced specific activity. Human HL deficiency in the context of a second factor causing hyperlipidemia is strongly associated with premature coronary artery disease.

Role of hepatic lipase in intermediate-density lipoprotein and small, dense low-density lipoprotein formation in hemodialysis patients

It has been reported that remnant lipoproteins and small, dense low-density lipoproteins (LDLs) are risk factors for cardiovascular disease. To determine whether these risk factors are present in hemodialysis (HD) patients who are suffering from a high incidence of atherosclerotic vascular disease, we measured concentrations of remnant lipoproteins and LDL particle diameter in HD patients and compared these with controls. We also measured lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) that play important roles in the generation of remnant lipoproteins and small, dense LDL, and we correlated these changes with plasma lipoprotein abnormalities in HD patients. Lipoproteins were separated by ultracentrifugation. Apoprotein B in very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) fractions were measured by a sensitive enzyme-linked immunosorbent assay method. The average LDL particle diameter was measured by gradient gel electrophoresis. Plasma triglyceride, total cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations were comparable between HD patients and controls, whereas LDL cholesterol was significantly lower in HD patients. The average LDL particle diameter was not significantly different between HD patients and controls. LDL particle diameter was inversely related to plasma triglyceride concentrations in all of the subjects. VLDL triglyceride, VLDL cholesterol, and VLDL apoprotein B were comparable between HD patients and controls. IDL triglyceride, IDL cholesterol, and IDL apoprotein B concentrations were all significantly increased in HD patients compared with those in controls. LPL mass was not altered, but HTGL activity was significantly decreased in HD patients. The HTGL activity was inversely related to IDL concentrations. These results suggest that a prominent characteristic of lipoprotein abnormalities in HD patients is a marked increase in IDL particle number. In addition, small, dense LDL is not associated with uremic dyslipidemia. Because HTGLs promote the conversion from IDL to LDL and the generation of lipid-poor LDL, a decrease in HTGL activity may contribute to the accumulation of IDL particle and may prevent small, dense LDL formation in HD patients.

Role of hepatic lipase in lipoprotein metabolism and atherosclerosis

Role of hepatic lipase in lipoprotein metabolism and atherosclerosis

Hepatic lipase facilitates the selective uptake of cholesteryl esters from remnant lipoproteins in apoE-deficient mice

We have investigated the role of hepatic lipase (HL) in remnant lipoprotein metabolism independent of lipolysis by using recombinant adenovirus to express native and catalytically inactive HL (HL-145G) in apolipoprotein (apo)E-deficient mice characterized by increased plasma concentrations of apoB-48-containing remnants. In the absence of apoE, the mechanisms by which apoB-48-containing remnants are taken up by either low density lipoprotein (LDL)-receptor or LDL-receptor-related protein (LRP) remain unclear. Overexpression of either native or catalytically inactive HL in apoE-deficient mice led to similar reductions (P > 0.5) in the plasma concentrations of cholesterol (41% and 53%) and non high density lipoprotein (HDL)-cholesterol (41% and 56%) indicating that even in the absence of lipolysis, HL can partially compensate for the absence of apoE in this animal model. Although the clearance of [3H]cholesteryl ether from VLDL was significantly increased (approximately 2-fold; P < 0. 02) in mice expressing native or inactive HL compared to luciferase controls, the fractional catabolic rates (FCR) of [125I-labeled] apoB- very low density lipoprotein (VLDL) in all three groups of mice were similar (P > 0.4, all) indicating selective cholesterol uptake. Hepatic uptake of [3H]cholesteryl ether from VLDL was greater in mice expressing either native HL (87%) or inactive HL-145G (72%) compared to luciferase controls (56%). Our combined findings are consistent with a role for HL in mediating the selective uptake of cholesterol from remnant lipoproteins in apoE-deficient mice, independent of lipolysis. These studies support the concept that hepatic lipase (HL) may serve as a ligand that mediates the interaction between remnant lipoproteins and cell surface receptors and/or proteoglycans. We hypothesize that one of these pathways may involve the interaction of HL with cell surface receptors, such as scavenger receptor (SR)-BI, that mediate the selective uptake of cholesteryl esters.

The role of hepatic lipase in lipoprotein metabolism and atherosclerosis.

In addition to its traditional role in the hydrolysis of lipoprotein triglycerides and phospholipids, recent studies have implicated hepatic lipase in other aspects of cellular lipid and/or lipoprotein metabolism and atherosclerosis. Hepatic lipase may serve as a ligand that mediates the interaction of lipoproteins to cell surface receptors and/or proteoglycans as well as modulating aortic lesion development in different animal models. Over the past several years significant advances have been made in our understanding of new, alternative mechanisms by which hepatic lipase may modulate lipoprotein metabolism and the development of atherosclerosis in vivo.

Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP)

The uptake of triglyceride-rich lipoproteins has been described as being mediated by apolipoprotein E and lipoprotein lipase (LpL). Proteoglycans, the LDL-receptor, and the LDL receptor-related protein (LRP) are the cellular acceptors. In addition to LpL, hepatic lipase (HL) has been shown to bind to LRP. In this study, the role of HL in lipoprotein uptake was investigated. Human chylomicrons and rabbit beta-VLDL were used as ligands for human hepatoma cells, primary human hepalocytes, normal and proteoglycan-deficient Chinese hamster ovary (CHO) cells, and normal and LDL receptor-deficient human fibroblasts. We show that HL induces stimulation of the uptake of chylomicrons and beta-VLDL into the different cell lines. HL is known to bind to heparan sulfate, and experiments on normal and proteoglycan-deficient CHO cells showed that cell surface proteoglycans are essential for HL-mediated uptake of lipoproteins. To exclude LDL receptor-mediated uptake. we performed experiments on LDL receptor-deficient fibroblasts that demonstrated that the LDL receptor was not important for the HL-mediated uptake of lipoproteins. Crosslinking experiments confirmed the binding of HL to LRP on the cell surface. To identify the region of HL involved in the interaction with LRP, we used a C-terminal fragment of LpL, known to inhibit LpL-mediated uptake. HL-mediated lipoprotein uptake was suppressed by this fragment. Our experiments indicate that HL, like LpL, can mediate the uptake of lipoproteins into cells, most probably via a C-terminal binding site. The uptake, initiated by proteoglycan binding, is mediated by LRP.

Role of hepatic lipase and cholesteryl ester transfer protein in HDL metabolism

Role of hepatic lipase and cholesteryl ester transfer protein in HDL metabolism

Role of hepatic lipase in the uptake and processing of chylomicron remnants in rat liver.

The participation of hepatic lipase in the initial uptake and processing of chylomicron remnants was studied in the isolated, perfused rat liver. Hepatic lipase activity was either reduced by preperfusion of livers with heparin or inhibited with specific rat hepatic lipase antibodies. [3H]palmitate-labeled chylomicron remnants were recirculated through control and treated livers for 15 min; the livers were then flushed, homogenized, and endosome-rich fractions were isolated. Depletion of hepatic lipase activity by both methods reduced the uptake of chylomicron remnants and hydrolysis of their component triglycerides by perfused rat livers, but at the same time significantly increased the rate of endocytosis of those chylomicron remnants taken up. We conclude that hepatic lipase facilitates, but is not essential for, the initial uptake of chylomicron remnants by rat liver. Furthermore, endocytosis of chylomicron remnants does not require binding to hepatic lipase or the associated hydrolysis of remnant lipids.

Different clearance of intravenously administered olive oil and soybean-oil emulsions: role of hepatic lipase

The elimination of two intravenously administered fat emulsions consisting of either 20% (wt:vol) soybean oil or 17% olive oil plus 3% soybean oil was studied in six normolipidemic young men according to a randomized crossover protocol. Slower elimination was found with the olive oil emulsion. A significantly lower maximal removal capacity (K1) and fractional catabolic rate (K2) were measured with olive oil emulsion (P < 0.05). Removal of olive oil emulsion was inversely related to hepatic lipase activity (r = -0.85; P < 0.05). Removal of soybean-oil emulsion was related to the initial plasma triglyceride concentration (r = -0.84; P < 0.05) but not to lipolytic activity. In vivo apolipoprotein C-II binding was similar for both emulsions. Therefore, hepatic lipase activity is more important in the elimination of olive oil emulsions than soybean-oil emulsions. The faster elimination of soybean-oil emulsions suggests an additional elimination pathway, such as the reticuloendothelial system.

The catabolism of very low density lipoproteins.

The lipolysis of very low density lipoproteins (VLDL) in vitro is a useful model for the study of the process of conversion of this triacylglycerol rich lipoprotein into low (LDL) and high (HDL) density lipoproteins. Data is reviewed to show that a portion of surface cholesterol and phospholipid which becomes redundant during lipolysis is lost from the lipoprotein. In the absence of HDL, the material forms lipoprotein-X (LpX) like vesicles which are not readily disrupted by HDL once they are formed. In the presence of HDL during lipolysis, the material is largely incorporated into HDL. The data is used to suggest a mechanism of formation of LpX-like vesicles in conditions where the production of surface remnants exceeds the capacity of HDL to disrupt them. Evidence is also provided to show that apolipoproteins (apo) C-II, C-III, and E are lost from VLDL and that this loss is primarily in association with a neutral core particle of HDL size which can subsequently exchange lipids and apolipoproteins with plasma HDL. Such a mechanism could account for the removal of apo E and excess cholesteryl ester which is necessary for conversion of VLDL to LDL. The role of hepatic lipase in this process remains speculative. Recent evidence is reviewed and used to propose that the enzyme may serve to rearrange the neutral core and surface composition of LDL and HDL subfractions to allow for the packaging of cholesteryl esters and the cycling of apolipoproteins.