We-W43:6 Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis (original) (raw)
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Journal of lipid research, 2014
The liver and the VLDL receptor (VLDLR) play major roles in TG and VLDL metabolism. However, the exact role of liver VLDLR is not well known because of the absence of or difficulty in detecting VLDLR in the liver. In this study, we demonstrate that fenofibrate, a PPARα agonist and widely used TG-lowering drug, markedly upregulated hepatic VLDLR, which is essential for lowering TG. This study also shows that the distinct regulatory roles of PPARα agonists on VLDLR in the liver and peripheral tissues including adipose tissues, heart, and skeletal muscles are due to the pattern of expression of PPARα. The in vivo portion of our study demonstrated that oral fenofibrate robustly increased liver VLDLR expression levels in hyperlipidemic and diabetic mice and significantly reduced the increase in serum TG observed in wt mice after feeding with high-fat diet (HFD) but not in Vldlr(-/-) mice or Pparα(-/-) mice. However, overexpression of mouse VLDLR in livers of Vldlr(-/-) mice significantly...
The Journal of Lipid Research, 2014
The expression of liver LDL receptor (LDLR) regulates human plasma LDL-cholesterol (LDL-C) homeostasis ( 1-3 ). Increased hepatic LDLR expression results in improved clearance of plasma LDL-C through receptor-mediated endocytosis, which is strongly associated with a decreased risk of developing cardiovascular disease in humans ( 4, 5 ). Thus far, many studies have demonstrated that intracellular cholesterol levels play a primary role in determination of hepatic LDLR expression levels through a negative feedback mechanism that controls gene transcription mediated by the sterolregulatory element (SRE) located in LDLR promoter and SRE binding proteins (SREBPs) ( 6, 7 ).
Pharmacological PPARβ/δ activation upregulates VLDLR in hepatocytes
Clínica e Investigación en Arteriosclerosis, 2019
The very low-density lipoprotein receptor (VLDLR) plays an important function in the control of serum triglycerides and in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the role of peroxisome proliferator-activated receptor (PPAR)/␦ activation in hepatic VLDLR regulation. Treatment of mice fed a high-fat diet with the PPAR/␦ agonist GW501516 increased the hepatic expression of Vldlr. Similarly, exposure of human Huh-7 hepatocytes to GW501516 increased the expression of VLDLR and triglyceride accumulation, the latter being prevented by VLDLR knockdown. Finally, treatment with another PPAR/␦ agonist increased VLDLR levels in the liver of wild-type mice, but not PPAR/␦-deficient mice, confirming the regulation of hepatic VLDLR by this nuclear receptor. Our results suggest that upregulation of hepatic VLDLR by PPAR/␦ agonists might contribute to the hypolipidemic effect of these drugs by increasing lipoprotein delivery to the liver. Overall, these findings provide new effects by which PPAR/␦ regulate VLDLR levels and may influence serum triglyceride levels and NAFLD development.
PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
Journal of Clinical Investigation, 2005
In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARγ dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARγ ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARγ target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARγ ligands regulate lipid metabolism and insulin sensitivity in adipocytes.
2003
Objective-To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se. Methods and Results-ApoE*3Leiden transgenic mice received either a high-cholesterol diet (HC) or HC containing fenofibrate (HCϩFF) resulting in 52% plasma cholesterol-lowering. In a separate low-cholesterol diet (LC) control group, plasma cholesterol was adjusted to the level achieved in the HCϩFF group. Low plasma cholesterol alone (assessed in LC) resulted in reduced atherosclerosis (lesion area, number and severity) and moderately decreased plasma serum amyloid-A (SAA) concentrations. Compared with LC, fenofibrate additively reduced lesion area, number and severity, and the total aortic plaque load. This additional effect in HCϩFF was paralleled by an extra reduction of aortic inflammation (macrophage content; monocyte adhesion; intercellular adhesion molecule-1 [ICAM-1], soluble vascular cell adhesion molecule-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), MCP-1, and NF-B expression), systemic inflammation (plasma SAA and fibrinogen levels), and by an upregulation of plasma apoE levels. Also, enhanced expression of ABC-A1 and SR-B1 in aortic macrophages may contribute to the antiatherosclerotic effect of fenofibrate by promoting cholesterol efflux. Conclusion-Fenofibrate reduces atherosclerosis more than can be explained by lowering total plasma cholesterol per se. Impaired recruitment of monocytes/macrophages, reduced vascular and systemic inflammation, and stimulation of cholesterol efflux may all contribute to these beneficial effect of fenofibrate. (Arterioscler Thromb Vasc Biol. 2006;26: 2322-2330.)
Experimental and Molecular Medicine, 2009
Peroxisome proliferator activated receptor (PPAR) gamma coactivator-1alpha (PGC-1alpha) may be implicated in cholesterol metabolism since PGC-1alpha co-activates estrogen receptor alpha (ERalpha) transactivity and estrogen/ERalpha induces the transcription of LDL receptor (LDLR). Here, we show that overexpression of PGC-1alpha in HepG2 cells represses the gene expression of LDLR and does not affect the ERalpha-induced LDLR expression. PGC-1alpha suppressed the LDLR promoter-luciferase (pLR1563- luc) activity regardless of cholesterol or functional sterol-regulatory element-1. Serial deletions of the LDLR promoter revealed that the inhibition by PGC-1alpha required the LDLR promoter regions between -650 bp and -974 bp. Phosphorylation of PGC-1alpha may not affect the suppression of LDLR expression because treatment of SB202190, a p38 MAP kinase inhibitor, did not reverse the LDLR down-regulation by PGC-1alpha. This may be the first report showing the repressive function of PGC-1alpha on gene expression. PGC-1alpha might be a novel modulator of LDLR gene expression in a sterol-independent manner, and implicated in atherogenesis.
PPARα controlling HDL metabolism and atherosclerosis
International Congress Series, 2004
Low serum high-density lipoprotein (HDL) cholesterol concentrations are a feature of the metabolic syndrome that is increasingly being recognized as an important risk factor for cardiovascular disease. HDL is a key mediator of reverse cholesterol transport (RCT), a pathway transporting cholesterol from extrahepatic cells and tissues to the liver for excretion. HDL metabolism is controlled by the interaction of its protein constituents, the apolipoproteins, such as apoA-I and apoA-II, with different enzymes (LCAT, HL, LPL), transfer proteins (CETP, PLTP,.. .) and lipoprotein receptors (ABCA-1, SR-BI,.. .). The level of expression of most of these proteins is partly controlled at the level of transcription by transcription factors, among which are the nuclear receptors. Nuclear receptors are activated by small lipophilic signalling molecules. Among these nuclear receptors, peroxisome proliferator-activated receptors were first identified to play a role in the control of lipid metabolism. In this paper, we will focus on the role of PPARa in HDL metabolism, its molecular action mechanism and its potential as pharmacological targets for future drug discovery.
Mechanisms of the Triglyceride- and Cholesterol-Lowering
2002
In humans, the precise mechanisms of the hypolipidemic action of fenofibrate, a peroxisome proliferator-activated receptor-␣ agonist, remain unclear. To gain insight on these mechanisms, we measured plasma lipids levels, lipids synthesis (hepatic de novo lipogenesis and cholesterol synthesis), and mRNA concentrations in circulating mononuclear cells (RT-PCR) of hydroxymethylglutaryl (HMG)-CoA reductase, LDL receptor, LDL receptor-related protein (LRP), scavenger receptor class B type I (SR-BI), ABCAI, and liver X receptor (LXR)-␣ in 10 control subjects and 9 hyperlipidemic type 2 diabetic patients. Type 2 diabetic subjects were studied before and after 4 months of fenofibrate administration. Fenofibrate decreased plasma triglycerides (P < 0.01) and total cholesterol (P < 0.05) concentrations and slightly increased HDL cholesterol (P < 0.05). Hepatic lipogenesis, largely enhanced in diabetic subjects (16.1 ؎ 2.1 vs. 7.5 ؎ 1.6% in control subjects, P < 0.01), was decreased by fenofibrate (9.8 ؎ 1.5%, P < 0.01). Fractional cholesterol synthesis was normal in diabetic subjects (3.5 ؎ 0.4 vs. 3.3 ؎ 0.5% in control subjects) and was unchanged by fenofibrate (3.5 ؎ 0.5%). Absolute cholesterol synthesis was, however, increased in diabetic subjects before and after fenofibrate (P < 0.05 vs. control subjects). HMG-CoA reductase, LDL receptor, LRP, and SR-BI mRNA concentrations were not different in type 2 diabetic and control subjects and were unchanged by fenofibrate. LXR-␣ mRNA levels were increased (P < 0.05) by fenofibrate. ABCAI mRNA concentrations, which were decreased in diabetic subjects (P < 0.05) before fenofibrate, were increased (P < 0.05) by fenofibrate to values comparable to those of control subjects. The plasma triglyceride-lowering effect of fenofibrate is explained in part by a decrease in hepatic lipogenesis, the moderate fall in total plasma cholesterol is not explained by a reduction of whole-body cholesterol synthesis, and the increase in LXR-␣ and ABCAI mRNA levels suggests that fenofibrate stimulated reverse cholesterol transport.