The Influence of Apolipoproteins on the Hepatic Lipase-mediated Hydrolysis of High Density Lipoprotein Phospholipid and Triacylglycerol

Hime, Neil J.; Barter, Philip J.; Rye, Kerry‐Anne

doi:10.1074/jbc.273.42.27191

Cited by 39 publications

(52 citation statements)

References 41 publications

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“…54 Hime et al 55 used reconstituted HDL particles to demonstrate that HL had a higher affinity to apoA-II-containing particles. In contrast, the V max for phospholipid hydrolysis was greater in apoA-I-containing particles.…”

Section: Dugi Et Al Adenovirus-mediated Expression Of Inactive Hlmentioning

confidence: 99%

In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL

Dugi

Amar

Haudenschild

et al. 2000

ATVB

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Abstract-To investigate the in vivo role that hepatic lipase (HL) plays in HDL metabolism independently of its lipolytic function, recombinant adenovirus (rAdV) expressing native HL, catalytically inactive HL (HL-145G), and luciferase control was injected in HL-deficient mice. At day 4 after infusion of 2ϫ10 8 plaque-forming units of rHL-AdV and rHL-145G-AdV, similar plasma concentrations were detected in postheparin plasma (HLϭ8.4Ϯ0.8 g/mL and HL-145Gϭ8.3Ϯ0.8 g/mL). Mice expressing HL had significant reductions of cholesterol (Ϫ76%), phospholipids (PL; Ϫ68%), HDL cholesterol (Ϫ79%), apolipoprotein (apo) A-I (Ϫ45%), and apoA-II (Ϫ59%; PϽ0.05 for all), whereas mice expressing HL-145G decreased their cholesterol (Ϫ49%), PL (Ϫ40%), HDL cholesterol (Ϫ42%), and apoA-II (Ϫ89%; PϽ0.005 for all) but had no changes in apoA-I. The plasma kinetics of 125 I-labeled apoA-I HDL, 131 I-labeled apoA-II HDL, and Key Words: hepatic lipase Ⅲ HDL metabolism Ⅲ lipolysis Ⅲ nonlipolytic function H epatic lipase (HL) is a 66-kDa lipolytic enzyme that is synthesized primarily by the liver. 1 It is anchored to the vascular endothelium present in the liver, ovaries, and adrenals via heparan sulfate proteoglycans and can be released into the circulation by the infusion of heparan sulfate. 2 HL hydrolyzes triglycerides and phospholipids present in chylomicron remnants, IDL, and HDL. Through its function as a lipolytic enzyme, HL plays a major role in the metabolism of circulating plasma lipoproteins.Several lines of evidence demonstrate the important role of HL in HDL metabolism. Patients with a genetic deficiency of HL have increased plasma levels of HDL cholesterol and phospholipids. 3,4 Increased HDL is also a hallmark of HLdeficient states induced by infusion of anti-HL antibodies 5,6 or genetic manipulation 7 or naturally present in different animal models. 8 Conversely, increased expression of HL in transgenic mice 9,10 and rabbits 11 significantly decreases plasma HDL concentrations. Similarly, adenovirus-mediated expression of human HL leads to marked reductions in HDL cholesterol [12][13][14] in different mouse models.In addition to its enzymatic action as a lipase, recent in vitro studies have suggested a separate role for HL in cellular lipoprotein metabolism by serving as a ligand that mediates the binding and uptake of lipoproteins via proteoglycans and/or receptor pathways. HL enhances the binding and/or uptake of chylomicrons, chylomicron remnants, and ␤-VLDL to different cell types in vitro, [15][16][17][18] a process that appears to require proteoglycans. 17 Most of these studies have investigated the HL-mediated interaction of apolipoprotein (apo)Bcontaining lipoproteins with cell surface receptors and/or proteoglycans. However, HL may play a similar role in promoting the cellular binding of HDL. [17][18][19] In the present article, we investigate, using recombinant adenovirus, potential mechanisms by which HL contributes to the metabolism of HDL in vivo by expressing native HL and catalytically inactive HL (HL-145G) in HL...

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Section: Dugi Et Al Adenovirus-mediated Expression Of Inactive Hlmentioning

confidence: 99%

In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL

Dugi

Amar

Haudenschild

et al. 2000

ATVB

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“…The ability of CETP to remodel HDL and mediate the dissociation of apoA-I is also influenced by the phospholipid composition of the particles (30), while triglyceride-enrichment enhances both HDL remodelling by PLTP and the dissociation of apoA-I (22). ApoA-I and apoA-II also regulate the hydrolysis of HDL phospholipids by EL, and the HL-mediated hydrolysis of HDL phospholipids and triglycerides (31,32).…”

Section: Remodelling and Hdl Subpopulation Heterogeneitymentioning

confidence: 99%

The metabolism and anti-atherogenic properties of HDL

Rye

Bursill

Lambert

et al. 2009

Journal of Lipid Research

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284

215

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Population studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties.-Rye, K-A., C. A. Bursill, G. Lambert, F. Tabet, and P. J. Barter. The metabolism and anti-atherogenic properties of HDL. J. Lipid Res. 2009. 50: S195-S200.Supplementary key words HDL remodelling • HDL subpopulations • HDL function HDL, the smallest and most dense of all plasma lipoproteins, consist of several distinct subpopulations of particles that vary in size, shape, density, surface charge, and composition. An inverse relationship between HDL levels and premature cardiovascular disease has been observed in many large-scale prospective studies (1, 2). This relationship is also evident in animal studies (3,4).HDL have several potentially anti-atherogenic properties. The best known of these is their ability to remove cholesterol from cells, such as macrophages in the artery wall, in the first step of the reverse cholesterol transport pathway (5). HDL also inhibit LDL oxidation (6), promote endothelial repair (7), improve endothelial function (8), have anti-thrombotic and anti-inflammatory properties (8, 9), and inhibit the binding of monocytes to the endothelium (10). In addition to preventing atherosclerotic lesion progression, HDL also promote lesion regression in animals (11, 12).This review presents evidence that several of the aforementioned anti-atherogenic functions of HDL are mediated by specific subpopulations of particles. To appreciate this functional diversity, it is important to understand something of the origins and heterogeneity of HDL subpopulations. ORIGINS OF HDLHDL originate as discoidal particles that are either secreted from the liver or assembled in the plasma from the individual constituents. Discoidal HDL consist of two or more apolipoprotein molecules complexed with phospholipids and unesterified cholesterol (Fig. 1A). These particles are excellent substrates for LCAT, the enzyme that generates most of the cholesteryl esters in plasma (13). Cholesteryl esters are extremely hydrophobic and partition into the center of the particles as they are formed. This converts discoidal HDL into the large spherical HDL particles that predominate in normal human plasma. It also depletes the HDL surface of cholesterol and establishes a concentration gradient down which ...

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“…These findings are consistent with previous in vitro (35) and in vivo (16,22,36) studies that indicate that the TG lipase and phospholipase activities of HL on apoB-Lps may not differ greatly. Potential mechanisms for the preference of HL-WT for the lipolysis of PL versus TG in lipoproteins include accessibility (PLs are on the surface of lipoprotein particles, whereas TGs are buried within the core) as well as lipid and apolipoprotein content [shown to be important for HDL (37)(38)(39)(40)(41)(42) and presumably for apoB-Lps as well]. Importantly, the decrease in plasma total TG and PL in LDLr-KO3HL-WT mice reflects not only the lipolytic function of HL-WT but also holoparticle uptake and/or selective lipid particle uptake of the apoB-Lps mediated by the ligand-binding function, which is present in HL-WT as well as HL-S145G mice.…”

Section: Discussionmentioning

confidence: 99%

Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice

Freeman

Amar

Shamburek

et al. 2007

Journal of Lipid Research

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To elucidate the separate contributions of the lipolytic versus ligand-binding functions of hepatic lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL -WT) with mice expressing inactive HL (HL -S145G) in a background lacking endogenous HL and the LDLr (LDLr-KO3HL-KO). HL-WT and HL-S145G reduced (P , 0.05 for all) cholesterol (55% vs. 20%), non-HDL-cholesterol (63% vs. 22%), and apolipoprotein B (apoB; 34% vs. 16%) by enhancing the catabolism of autologous 125 I-apoB-intermediate density lipoprotein (IDL)/LDL (fractional catabolic rate in day 21 : 6.07 6 0.25, LDLr-KO3HL-WT; 4.76 6 0.30, LDLr-KO3HL-S145G; 3.70 6 0.13, LDLr-KO3HL-KO); HL-WT had a greater impact on the concentration, composition, particle size, and catabolism of apoB-containing lipoproteins (apoB-Lps) and HDL. Importantly, consistent with the changes in apoB-Lps, atherosclerosis in LDLr-KO3HL-KO mice fed a regular chow diet (RCD) was reduced by both HL-WT and HL-S145G (by 71% and 51% in cross-sectional analysis, and by 85% and 67% in en face analysis; P , 0.05 for all). These data identify physiologically relevant but distinct roles for the lipolytic versus ligand-binding functions of HL in apoBLp metabolism and atherosclerosis and demonstrate that their differential effects on these processes are mediated by changes in catabolism via non-LDLr pathways. These changes, evident even in the presence of apoE, establish an antiatherogenic role of the ligand-binding function of HL in LDLr-deficient mice. Hepatic lipase (HL) is a multifunctional protein with a complex role in lipoprotein metabolism. It is synthesized and secreted primarily by hepatocytes and functions not only as a lipolytic enzyme that hydrolyzes triglycerides (TGs) and phospholipids (PLs) in apolipoprotein Bcontaining lipoproteins (apoB-Lps) and HDL but also as a ligand or coreceptor that facilitates the cellular uptake of lipoproteins and lipoprotein lipids (1-9). These different functions of HL, which facilitate not only plasma lipoprotein metabolism but also cellular lipid uptake, may have variable effects on atherosclerosis; indeed, human and animal studies appear to support both a proatherogenic and an antiatherogenic role for HL (6,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).The mechanisms underlying these variable and sometimes opposing atherosclerosis outcomes are not completely understood. The finding that HL in arterial wall lesions enhances atherosclerosis without altering plasma lipoprotein lipid levels (16, 24) provided partial insight into these discrepancies. Another possible yet not fully investigated explanation for these conflicting data may be the potentially differential effects of the lipolytic versus ligandbinding functions of HL on the plasma concentrations and subclass distributions of the different plasma lipoproteins, which in turn may differentially affect atherosclerosis. Initial...

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The Influence of Apolipoproteins on the Hepatic Lipase-mediated Hydrolysis of High Density Lipoprotein Phospholipid and Triacylglycerol

Cited by 39 publications

References 41 publications

In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL

In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL

The metabolism and anti-atherogenic properties of HDL

Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice

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