Peroxisome proliferator-activated receptor γ stimulation of adipocyte ApoE gene transcription mediated by the liver receptor X pathway

Abstract

Peroxisome proliferator-activated receptor (PPARγ) 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 PPARγ agonists. The current studies investigate the molecular mechanism for PPARγ 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 PPARγ agonists. The response of the apoE gene to treatment with PPARγ agonists was delayed beyond 12 h suggesting the involvement of an intermediary pathway. The combined addition of PPARγ 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 PPARγ agonist. Chromatin immunoprecipitation analyses performed using isolated adipocytes, or adipose tissue from mice treated with PPARγ agonists, showed increased LXR binding to the apoE gene after PPARγ agonist treatment. Knockdown of LXR expression completely eliminated the increase in apoE message, protein, and triglyceride in response to PPARγ 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 PPARγ- LXR-apoE regulatory cascade could be an important molecular link for cross-talk between adipocyte triglyceride and cholesterol homeostasis. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.