The hepatic uptake of VLDL in lrpldlrvldlr mice is regulated by LPL activity and involves proteoglycans and SR-BI

Abstract

LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Administration of an adenovirus expressing LPL (AdLPL) into lrp 2 ldlr 2/2 vldlr 2/2 mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, inhibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their remnants positively correlated with LPL activity. This hepatic association was independent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp 2 ldlr 2/2 vldlr 2/2 mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI.-Hu, L., C. C. van LPL is the key enzyme responsible for the hydrolysis of triglycerides (TGs) in TG-rich lipoproteins such as chylomicrons and VLDL (1, 2). During lipolysis, the lipoproteins are reduced in size and enriched with apolipoprotein E (apoE). Subsequently, their core remnants are taken up mainly by the liver via apoE-recognizing receptors [i.e., the LDL receptor (LDLr) and the LDLr-related protein (LRP)] (2). Therefore, mice deficient for the LDLr and hepatic LRP show marked accumulation of TG-rich lipoprotein remnants (3). Although core remnants may be directly internalized via the LDLr, the binding and internalization via the LRP is thought to involve previous binding of core remnants to heparan sulfate proteoglycans (HSPGs) in the space of Disse via heparin binding proteins such as apoE (4, 5).The third major apoE-recognizing receptor, the VLDL receptor (VLDLr), is expressed abundantly in tissues active in fatty acid metabolism [i.e., heart, skeletal muscle,

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

“…Reductions in plasma cholesterol have also been observed in other mouse models in which LPL expression is increased either directly ( 41-43 ) or indirectly ( 44 ). The cholesterol-lowering effects were observed with increases in LPL that are comparable ( ‫ف‬ 2-to 3-fold) to those associated with inactivation of ANGPTL3 in the present study ( 43 ). Therefore, it is possible that an increase in LPL promotes the clearance of ApoB-containing lipoproteins either by catalyzing changes in lipid content that increase binding of the lipoprotein particles to nonspecifi c binding sites on the cell surface, such as proteoglycans ( 45 ), or by acting as a molecular bridge between lipoproteins and cell surface receptors or proteoglycans ( 46 ), as originally proposed by Felts, Itakura, and Crane ( 47 ).…”

Scavenger receptor BI facilitates hepatic very low density lipoprotein production in mice

“…It has also been established by in vitro as well as in vivo studies that SR-BI and its human ortholog Cla-1 can bind apoB-containing lipoproteins and mediate their internalization (3)(4)(5)(6)20 ). This property of SR-BI might depend on the physiological context as hepatic overexpression of SR-BI in hapoB transgenic mice ( 21 ) or attenuated expression in LDLR knockout ( 22 ) mice did not affect the LDL catabolic rate.…”

Roles of Lipoproteins and Apolipoproteins in Particle Formation of Hepatitis C Virus

“…Although several reports have shown that exchangeable apolipoproteins, especially ApoE and ApoC3, participate in the assembly and secretion of VLDL, the precise roles of the apolipoproteins are largely unknown [74]. heparan sulfate proteoglycan (HSPG), interacting with or without lipoprotein receptors, including LDLR and SR-B1 [75]. The interaction between exchangeable apolipoproteins and lipoproteins confers stability and hydrophilicity through exchange with other high-affinity apolipoproteins [65].…”