PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
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DOI：
10.1172/jci24130
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发表时间：
2005-08-01
影响因子：
15.9
通讯作者：
Lazar, MA
中科院分区：
文献类型：
--
作者：
Chui, PC;Guan, HP;Lazar, MA
脂肪组织除了具有储存能量的作用外，还积累胆固醇。脂肪细胞中胆固醇和甘油三酯的浓度密切相关，但人们对脂肪细胞中胆固醇代谢的调节机制知之甚少。在此，我们报道抗糖尿病噻唑烷二酮类药物 (TZD) 和核受体 PPAR γ 的其他配体通过促进培养的小鼠脂肪细胞中 OLR1 基因上的共激活剂与辅阻遏物的交换，显着上调脂肪细胞中的氧化 LDL 受体 1 (OLR1)。 TZD 显着刺激脂肪细胞摄取氧化低密度脂蛋白 (oxLDL)，而这需要 OLR1。 TZD 治疗或腺病毒基因传递导致 OLR1 表达增加，显着增加脂肪细胞胆固醇含量并增强脂肪酸摄取。肥胖时白色脂肪组织中的 OLR1 表达增加，并通过体内 PPAR γ 配体治疗进一步诱导。使用 TZD 治疗的瘦型和肥胖型糖尿病动物的血清 oxLDL 水平均有所降低。这些数据将 OLR1 确定为脂肪细胞中的新型 PPAR γ 靶基因。虽然脂肪组织在胆固醇和 oxLDL 代谢中的生理作用仍有待确定，但 OLR1 的诱导是 PPAR γ 配体调节脂肪细胞脂质代谢和胰岛素敏感性的潜在手段。
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 PPAR gamma 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 PPAR gamma 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 PPAR gamma 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 PPAR gamma ligands regulate lipid metabolism and insulin sensitivity in adipocytes.