Yue Lili, Mazzone Theodore
Departments of Medicine, Pharmacology, and Human Nutrition, University of Illinois, Chicago, Illinois 60612.
J Biol Chem. 2009 Apr 17;284(16):10453-61. doi: 10.1074/jbc.M808482200. Epub 2009 Feb 13.
Peroxisome proliferator-activated receptor (PPARgamma) agonists increase insulin sensitivity in humans and are useful for treating human diabetes. Treatment with these agonists leads to increased apoE expression and triglyceride accumulation in adipocytes. The importance of apoE for adipocyte triglyceride accumulation is demonstrated by observations that triglyceride accumulation is impaired in apoE knockout adipocytes treated with PPARgamma agonists. The current studies investigate the molecular mechanism for PPARgamma stimulation of the adipocyte apoE gene and demonstrate that the liver receptor X (LXR) response element within an apoE gene downstream enhancer is required for the apoE response to PPARgamma agonists. The response of the apoE gene to treatment with PPARgamma agonists was delayed beyond 12 h suggesting the involvement of an intermediary pathway. The combined addition of PPARgamma and LXR agonists did not increase apoE response beyond that observed with addition of either alone. Deletion or mutation of the LXR response element completely eliminated the adipocyte apoE gene response to a PPARgamma agonist. Chromatin immunoprecipitation analyses performed using isolated adipocytes, or adipose tissue from mice treated with PPARgamma agonists, showed increased LXR binding to the apoE gene after PPARgamma agonist treatment. Knockdown of LXR expression completely eliminated the increase in apoE message, protein, and triglyceride in response to PPARgamma stimulation. The LXR response element has been previously shown to mediate sterol responsiveness of the apoE gene, and apoE expression plays an important role in adipocyte triglyceride balance. The current observations suggest that the PPARgamma-LXR-apoE regulatory cascade could be an important molecular link for cross-talk between adipocyte triglyceride and cholesterol homeostasis.
过氧化物酶体增殖物激活受体（PPARγ）激动剂可提高人类的胰岛素敏感性，对治疗人类糖尿病很有用。用这些激动剂治疗会导致载脂蛋白E（apoE）表达增加以及脂肪细胞中甘油三酯的积累。apoE对脂肪细胞甘油三酯积累的重要性通过以下观察得以证明：在用PPARγ激动剂处理的apoE基因敲除脂肪细胞中，甘油三酯积累受到损害。当前的研究调查了PPARγ刺激脂肪细胞apoE基因的分子机制，并证明apoE基因下游增强子内的肝脏X受体（LXR）反应元件是apoE对PPARγ激动剂产生反应所必需的。apoE基因对PPARγ激动剂治疗的反应延迟超过12小时，这表明存在中间途径的参与。联合添加PPARγ和LXR激动剂并没有使apoE反应超过单独添加任何一种激动剂时所观察到的反应。LXR反应元件的缺失或突变完全消除了脂肪细胞apoE基因对PPARγ激动剂的反应。使用分离的脂肪细胞或用PPARγ激动剂处理的小鼠的脂肪组织进行的染色质免疫沉淀分析表明，PPARγ激动剂处理后，LXR与apoE基因的结合增加。敲低LXR表达完全消除了对PPARγ刺激的apoE信使、蛋白质和甘油三酯的增加。LXR反应元件先前已被证明可介导apoE基因的固醇反应性，并且apoE表达在脂肪细胞甘油三酯平衡中起重要作用。当前的观察结果表明，PPARγ-LXR-apoE调节级联可能是脂肪细胞甘油三酯与胆固醇稳态之间相互作用的重要分子联系。
