PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1.
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 PPARgamma 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 PPARgamma 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 PPARgamma 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 PPARgamma ligands regulate lipid metabolism and insulin sensitivity in adipocytes.
Chui
Patricia C
PC
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA.
Guan
Hong-Ping
HP
Lehrke
Michael
M
Lazar
Mitchell A
MA
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D011973:Receptors, LDL / Q000096:biosynthesis*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D045162:Thiazolidinediones / Q000494:pharmacology
D005227:Fatty Acids; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; C495138:Olr1 protein, mouse; D047495:PPAR gamma; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D045162:Thiazolidinediones; C099252:oxidized low density lipoprotein; D002784:Cholesterol