Hepatic lipase may act as a ligand in the uptake of artificial chylomicron remnant-like particles by isolated rat hepatocytes.

Diard, P; Malewiak, Marie-Irène; Lagrange, Dominique; Griglio, S.

doi:10.1042/bj2990889

Cited by 86 publications

(79 citation statements)

References 45 publications

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“…1,39 -41 In addition, it enhances cell association of triglyceride-rich lipoprotein remnants by initiating their binding to cell surface heparin sulfate proteoglycans. 9,42 Our results showing significantly reduced levels of small VLDLs and IDLs in HL transgenic rabbits are consistent with these functions of HL and with earlier suggestions that endogenous HL deficiency in rabbits may contribute to their hyperlipidemic response to cholesterol feeding. 43,44 The accumulation of very large lipoproteins in these animals suggests that HL does not interact significantly with these particles.…”

Section: Discussionsupporting

confidence: 79%

Overexpression of Human Hepatic Lipase and ApoE in Transgenic Rabbits Attenuates Response to Dietary Cholesterol and Alters Lipoprotein Subclass Distributions

Barbagallo

Fan

Blanche

et al. 1999

ATVB

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Abstract-The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholesterol was compared with the response of nontransgenic control rabbits. Supplementation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 weeks resulted in markedly increased levels of plasma cholesterol and VLDL and IDL in control rabbits as expected. Expression of either HL or apoE reduced plasma cholesterol response by 75% and 60%, respectively. The HL transgenic rabbits had substantial reductions in medium and small VLDL and IDL fractions but not in larger VLDL. LDL levels were also reduced, with a shift from larger, more buoyant to smaller, denser particles. In contrast, apoE transgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Studies in animal models and HL-deficient humans 5-8 suggested that HL is involved in the conversion of IDLs to LDLs, and in the catabolism of large lipid-rich HDLs (reviewed in Reference 1). HL also enhances the direct binding and uptake of cholesteryl ester-rich VLDL and chylomicron remnants by hepatocytes. 9 Human apoE is a 299 -amino-acid glycoprotein present mainly in triglyceride-rich particles (chylomicrons, VLDLs, and IDLs) and large HDLs. A major role of apoE in plasma lipid transport is to mediate the binding and clearance of remnant lipoproteins and large cholesterol-rich HDLs to receptors in hepatic and peripheral cells. 2,10,11 To determine whether the physiological roles of HL and apoE in plasma cholesterol and lipoprotein metabolism are complementary, we generated transgenic lines of rabbits overexpressing the corresponding human proteins. Rabbits were used because they are naturally deficient in HL and they have relatively reduced levels of apoE compared with other species. 12, 13 We previously found that overexpression of HL in transgenic rabbits resulted in a reduction in IDLs and all subclasses of HDLs in chow-fed rabbits, as well as a 2-fold reduction in plasma cholesterol, in comparison with nontransgenic controls. 14,15 Overexpression of apoE in transgenic rabbits was shown to decrease VLDL levels; this effect was due to an increased affinity of large apoE-rich remnants for the LDL receptor that was related to increased chylomicron clearance rate. 16 Although VLDLϩIDL and LDLs are commonly defined as lipoproteins of density Ͻ1.019 and 1.019 to 1.063 g/mL, respectively, among these intervals it is possible to recognize several heterogeneous subclasses, differing in size, density, flotation rate, electrophoretic mobility, and chemical composition. [17][18][19][20][21][22][23][24][25] We previously used density-gradient ultracentrifugation (DGUC) and electrophoresis in polyacrylamide gradient gels to demonstrate the existence of multiple distinct subclasses of VLDLs and IDLs in humans. 19,20 By injecting human lipoproteins into rats, we documented different met-

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Section: Discussionsupporting

confidence: 79%

Overexpression of Human Hepatic Lipase and ApoE in Transgenic Rabbits Attenuates Response to Dietary Cholesterol and Alters Lipoprotein Subclass Distributions

Barbagallo

Fan

Blanche

et al. 1999

ATVB

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“…HL has also been shown to act as a ligand in the uptake of lipoproteins (Diard et al 1994;Kounnas et al 1995;Krapp et al 1996) and due to its structural similarity to LPL this was not unexpected. Nykjaer et al (1994) showed that LRP directly binds to HL and LPL, and that P-VLDL, as a model lipoprotein, interacts directly with both lipases.…”

Section: Effect Of Lipases On Lipoprotein Uptake Into Cellsmentioning

confidence: 99%

Lipoprotein lipase (EC3.1.1.34) targeting of lipoproteins to receptors

Beisiegel

Heeren

1997

Proc. Nutr. Soc.

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“…Cell-surface receptors, including the LDL receptor (LDLR), low density lipoprotein receptor-related protein (LRP), and SR-BI, as well as cellsurface proteoglycans, have been implicated in this process (15-17, 20, 22). Initial evidence for a ligand-binding function of HL in cellular lipid uptake and lipoprotein metabolism, independent of the lipolytic function of the lipase, came from studies using heat-inactivated HL (18) and anti-HL antibodies (19,23). These data were confirmed and extended by in vivo experiments that either infused the receptor-associated protein (RAP) and anti-HL/LDLR antibodies (24) or expressed a catalytically inactive form of HL, HL-S145G, in various mouse models.…”

mentioning

confidence: 99%

“…In this respect, HL could serve as a ligand that facilitates these interactions or, alternatively, could function as a coreceptor. In vitro studies have demonstrated that HL enhances the binding and/or uptake of chylomicrons, chylomicron remnants, ␤-very low density protein (VLDL), and LDL (15)(16)(17)(18)(19)(20) as well as HDL cholesterol (HDL-C) (18, 20 -22) in a variety of cell types. Cell-surface receptors, including the LDL receptor (LDLR), low density lipoprotein receptor-related protein (LRP), and SR-BI, as well as cellsurface proteoglycans, have been implicated in this process (15-17, 20, 22).…”

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confidence: 99%

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

González-Navarro

Zhang

Amar

et al. 2004

Journal of Biological Chemistry

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To investigate the separate contributions of the lipolytic versus ligand-binding function of hepatic lipase (HL) to plasma lipoprotein metabolism and atherosclerosis, we compared mice expressing catalytically active wild-type HL (HL-WT) and inactive HL (HL-S145G) with no endogenous expression of mouse apoE or HL (E-KO ؋ HL-KO, where KO is knockout). HL-WT and HL-S145G reduced plasma cholesterol (by 40 and 57%, respectively), non-high density lipoprotein cholesterol (by 48 and 61%, respectively), and apoB (by 36 and 44%, respectively) (p < 0.01), but only HL-WT decreased high density lipoprotein cholesterol (by 67%) and apoA-I (by 54%). Compared with E-KO ؋ HL-KO mice, both active and inactive HL lowered the pro-atherogenic lipoproteins by enhancing the catabolism of autologous 125 I-apoB very low density/intermediate density lipoprotein (VLDL/ IDL) (fractional catabolic rates of 2.87 ؎ 0.04/day for E-KO ؋ HL-KO, 3.77 ؎ 0.03/day for E-KO ؋ HL-WT, and 3.63 ؎ 0.09/day for E-KO ؋ HL-S145G mice) and 125 IapoB-48 low density lipoprotein (LDL) (fractional catabolic rates of 5.67 ؎ 0.34/day for E-KO ؋ HL-KO, 18.88 ؎ 1.72/day for E-KO ؋ HL-WT, and 9.01 ؎ 0.14/day for E-KO ؋ HL-S145G mice). In contrast, the catabolism of apoE-free, 131 I-apoB-100 LDL was not increased by either HL-WT or HL-S145G. Infusion of the receptor-associated protein (RAP), which blocks LDL receptor-related protein function, decreased plasma clearance and hepatic uptake of 131 I-apoB-48 LDL induced by HL-S145G. Despite their similar effects on lowering proatherogenic apoB-containing lipoproteins, HL-WT enhanced atherosclerosis by up to 50%, whereas HL-S145G markedly reduced aortic atherosclerosis by up to 96% (p < 0.02) in both male and female E-KO ؋ HL-KO mice. These data identify a major receptor pathway (LDL receptor-related protein) by which the ligand-binding function of HL alters remnant lipoprotein uptake in vivo and delineate the separate contributions of the lipolytic versus ligand-binding function of HL to plasma lipoprotein size and metabolism, identifying an anti-atherogenic role of the ligand-binding function of HL in vivo.Hepatic lipase (HL) 1 is a 64-kDa lipolytic enzyme that plays a major role in lipoprotein metabolism. It is synthesized and secreted primarily by hepatocytes (1, 2) and is anchored to the vascular endothelium via heparin sulfate proteoglycans. HL functions both as an acylglycerol hydrolase and a phospholipase, hydrolyzing triglycerides (TG) and phospholipids (PL) in chylomicron remnants and intermediate density lipoproteins (IDL). In humans, HL plays a major role in determining low density lipoprotein (LDL) subclass distribution, which may in turn modulate atherogenic risk (3-7). HL is also an important determinant of high density lipoprotein (HDL) concentration and subclass distribution, converting the phospholipid-rich HDL 2 to HDL 3 (3, 4, 8 -14).In addition to its function as a lipolytic enzyme, HL has a separate role in lipoprotein metabolism by directly facilitating the uptake of lipoproteins and lipoprotein lip...

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Hepatic lipase may act as a ligand in the uptake of artificial chylomicron remnant-like particles by isolated rat hepatocytes.

Cited by 86 publications

References 45 publications

Overexpression of Human Hepatic Lipase and ApoE in Transgenic Rabbits Attenuates Response to Dietary Cholesterol and Alters Lipoprotein Subclass Distributions

Overexpression of Human Hepatic Lipase and ApoE in Transgenic Rabbits Attenuates Response to Dietary Cholesterol and Alters Lipoprotein Subclass Distributions

Lipoprotein lipase (EC3.1.1.34) targeting of lipoproteins to receptors

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

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