Role of the Low Density Lipoprotein (LDL) Receptor Pathway in the Metabolism of Chylomicron Remnants

Ishibashi, Shun; Perrey, Stéphane; Chen, Zhong; Osuga, Jun-ichi; Shimada, Masako; Ohashi, Ken; Harada, Kenji; Yazaki, Yoshio; Yamada, Nobuhiro

doi:10.1074/jbc.271.37.22422

Cited by 108 publications

(47 citation statements)

References 46 publications

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“…These observations are consistent with our previous findings that the LDLR plays a pivotal role in the metabolism of chylomicron (27). In the present study, however, no significant difference was observed in the plasma excursion of retinyl ester between the LDLRKO mice with and without the apo E transgene (Fig.…”

Section: Discussionsupporting

confidence: 94%

Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.

Osuga¹,

Yonemoto²,

Yamada³

et al. 1998

J. Clin. Invest.

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Apo E is a key molecule in the lipoprotein metabolism; thus, genetic manipulation of apo E may prove useful in the treatment of hypercholesterolemia. To test the feasibility of this idea, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpress the rat apo E transgene ( ETg ϩ / ϩ :LDLRKO ) , and compared their plasma lipoprotein profiles with those of nonexpressing LDLR knockout mice ( ETg Ϫ / Ϫ :LDLRKO ) . On a normal chow diet, the mean plasma cholesterol level of ETg ϩ / ϩ :LDLRKO mice was significantly lower than that of ETg Ϫ / Ϫ :LDLRKO mice (189 versus 240 mg/dl, P Ͻ 0.01). The LDL fraction was selectively reduced in the ETg ϩ / ϩ :LDLRKO mice. Despite the challenge with an atherogenic diet, cholesterol lowering was persistently observed and fatty streak lesions in the aortic sinus were significantly suppressed in the mice overexpressing apo E. These results imply that stimulation of hepatic production of apo E may be used as a promising adjunctive therapy for homozygous familial hypercholesterolemia.

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Section: Discussionsupporting

confidence: 94%

Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.

Osuga¹,

Yonemoto²,

Yamada³

et al. 1998

J. Clin. Invest.

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“…It should be noted that ApoE lipoproteins are unusual; they are cholesterol enriched and lack ApoE. However, their rapid turnover in these mice, as opposed to the slow turnover of CM-RE in ApoE knock-out mice (55), suggests that the particles have acquired ApoE from their recipients. Thus, our data strongly imply that much of the lipoprotein core lipid uptake into the heart occurs via lipid shedding.…”

Section: Discussionmentioning

confidence: 94%

Chylomicron- and VLDL-derived Lipids Enter the Heart through Different Pathways

Bharadwaj

Hiyama

et al. 2010

Journal of Biological Chemistry

105

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Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart-specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36 ؊/؊ ), and double knock-out (hLpL0/Cd36 ؊/؊ -DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 ؎ 3.8; hLpL0, 36.2 ؎ 3.5; Cd36 ؊/؊ , 57.7 ؎ 5.5 nmol/g, p < 0.05) and an additive effect was observed in the DKO (20.2 ؎ 1.4 nmol/g, p < 0.05). Myocardial VLDL-triglyceride (TG) uptake was reduced in the hLpL0 (31 ؎ 6%) and Cd36 ؊/؊ (47 ؎ 4%) mice with an additive reduction in the DKO (64 ؎ 5%) compared with control. However, LpL but not CD36 deficiency decreased VLDL-cholesteryl ester uptake. Endogenously labeled mouse chylomicrons were produced by tamoxifen treatment of ␤-actin-MerCreMer/ LpL flox/flox mice. Induced loss of LpL increased TG levels >10-fold and reduced HDL by >50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by ϳ70% and retinyl ester by ϳ50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDLderived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins.Under normal physiological conditions, myocardial energy demands are predominantly met by fatty acid (FA) 3 oxidation (Ͼ70%) with the remaining energy provided by glucose, lactate, and ketones. The majority of the lipid entering cardiac cells is diverted toward FA utilization (1) with some being stored or used for structural requirements. FAs are delivered to the heart from two sources: (a) FAs esterified as triglyceride (TG) contained in circulating lipoproteins and liberated by lipoprotein lipase (LpL)-mediated lipolysis, and (b) non-esterified FA, referred to as free FAs (FFAs), bound to serum albumin. The mechanisms responsible for the uptake of FAs by the heart, or any organ, are incompletely understood. Specifically, the importance of receptor-mediated uptake versus diffusion of FAs across membranes is under debate. Studies in cardiomyocytes (2-4) and other cells (5, 6) have suggested that uptake of FAs by cultured cells can occur via two pathways (7,8). A low capacity but high affinity uptake pathway thought to represent receptormediated uptake is operative at FFA/albumin ratios normally found in the plasma (5). At higher FFA concentrations, uptake occurs via a lower affinity non-saturable process (9, 10); this has been studied in synthetic membranes and thought to represent non-receptor uptake also referred to as "flip-flop" (11-13). Several proteins including fatty acid translocase (FAT/ ...

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“…The LDL receptor (LDL-R) accounts for most of LDL removal and contributes to part of the uptake of chylomicron remnants (4,5). This highly informative endocytic receptor prototype nevertheless leaves two unsolved issues regarding apoB-containing lipoprotein clearance.…”

Section: Triglyceride (Tg)mentioning

confidence: 99%

Lipolysis Stimulated Lipoprotein Receptor

Yen

Roitel²,

Bonnard³

et al. 2008

Journal of Biological Chemistry

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The lipolysis-stimulated lipoprotein receptor, LSR, is a multimeric protein complex in the liver that undergoes conformational changes upon binding of free fatty acids, thereby revealing a binding site(s) that recognizes both apoB and apoE. Complete inactivation of the LSR gene is embryonic lethal in mice. Here we show that removal of a single LSR allele (LSR ؊/؉ ) caused statistically significant increases in both plasma triglyceride and cholesterol levels, a 2-fold increase in plasma triglyceride changes during the post-prandial phase, and delayed clearance of lipid emulsions or a high fat meal. The longer postprandial lipoprotein clearance time observed in LSR ؊/؉ mice was further increased in LSR ؊/؉ mice lacking functional low density lipoprotein (LDL) receptors. LSR ؊/؉ mice placed on a Westerntype diet displayed higher plasma triglycerides and cholesterol levels, increased triglyceride-rich lipoproteins and LDL, and increased aorta lipid content, as compared with control mice on the same diet. Furthermore, a direct correlation was observed between the hyperlipidemia and weight gain but only in the LSR ؊/؉ mice. Knockdown of LSR expression by small interfering RNA in mouse Hepa1-6 cells led to decreased internalization of both DiI-labeled cyclohexanedione-LDL and very low density lipoprotein in the presence of oleate. These data led us to conclude that LSR contributes to the physiological clearance of atherogenic triglyceride-rich lipoproteins and LDL. We propose that LSR cooperates with the LDL receptor in the final hepatic processing of apoB-containing lipoproteins and represents a novel therapeutic target for the treatment of hyperlipidemia associated with obesity and atherosclerosis. Triglyceride (TG)2 -rich apoB-containing lipoproteins are produced by the liver as VLDL or by the intestine as chylomicrons (1). Both types of particles deliver their TG load to peripheral tissues through interactions with lipoprotein lipase (LpL) anchored to capillary endothelium heparan sulfate proteoglycans (HSPGs) (1). The residual cholesterol enriched inter-mediate density lipoprotein (IDL) and LDL for VLDL, and chylomicrons remnants are then removed from the circulation by hepatocytes. Clearance of these lipoproteins in the liver is a complex process through which the particles enter the space of Disse, bind to HSPGs, acquire apoE, and interact with hepatic lipase and LpL (2). After this, the residual particles are delivered to endocytic receptors for cellular internalization and degradation (3).The LDL receptor (LDL-R) accounts for most of LDL removal and contributes to part of the uptake of chylomicron remnants (4, 5). This highly informative endocytic receptor prototype nevertheless leaves two unsolved issues regarding apoB-containing lipoprotein clearance. First, in the absence of functional LDL-R, the amount of LDL cleared daily is 2-fold greater than that of subjects with normal LDL-R activity (6) and has been shown to take place in the liver (7). Second, the clearance of intestinally derived chylomicron remnan...

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Role of the Low Density Lipoprotein (LDL) Receptor Pathway in the Metabolism of Chylomicron Remnants

Cited by 108 publications

References 46 publications

Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.

Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.

Chylomicron- and VLDL-derived Lipids Enter the Heart through Different Pathways

Lipolysis Stimulated Lipoprotein Receptor

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