PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
Patricia C. Chui, … , Michael Lehrke, Mitchell A. Lazar
Patricia C. Chui, … , Michael Lehrke, Mitchell A. Lazar
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2244-2256. https://doi.org/10.1172/JCI24130.
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Research Article Metabolism

PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1

Abstract

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.

Authors

Patricia C. Chui, Hong-Ping Guan, Michael Lehrke, Mitchell A. Lazar

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Figure 3

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The proximal PPARγ binding site in the OLR1 promoter is the predominant ...
The proximal PPARγ binding site in the OLR1 promoter is the predominant PPRE. (A) Identification of putative PPARγ binding sites (underlined) in the OLR1 promoter. Letters A–D correspond to arrowheads in Figure 2A. (B) DNA mobility shift assay showing the binding of PPARγ/RXRα to wild-type and mutant oligonucleotide probes corresponding to the putative PPARγ binding sites underlined in A. Control lane reactions did not contain PPARγ/RXRα. Mutant oligonucleotides contain point mutations in the putative PPARγ binding site; for specific mutations, see Methods. (C) Luciferase activity of OLR1 reporter constructs containing mutations in the PPARγ binding sites. Site-specific mutations were made in the longest OLR1 reporter construct (–1,738; Figure 2A). Data represent the fold induction of luciferase activity over the basal activity of the empty pGL2 vector and are expressed as mean ± SEM (n = 3 per condition). *P < 0.01 compared with transfected cells treated with vehicle.