Peroxisome Proliferator-activated Receptor γ Stimulation of Adipocyte ApoE Gene Transcription Mediated by the Liver Receptor X Pathway

Abstract

Peroxisome proliferator-activated receptor (PPAR␥) 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 PPAR␥ agonists. The current studies investigate the molecular mechanism for PPAR␥ 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 PPAR␥ agonists. The response of the apoE gene to treatment with PPAR␥ agonists was delayed beyond 12 h suggesting the involvement of an intermediary pathway. The combined addition of PPAR␥ 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 PPAR␥ agonist. Chromatin immunoprecipitation analyses performed using isolated adipocytes, or adipose tissue from mice treated with PPAR␥ agonists, showed increased LXR binding to the apoE gene after PPAR␥ agonist treatment. Knockdown of LXR expression completely eliminated the increase in apoE message, protein, and triglyceride in response to PPAR␥ 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 PPAR␥-LXR-apoE regulatory cascade could be an important molecular link for cross-talk between adipocyte triglyceride and cholesterol homeostasis. PPAR␥2 is highly expressed in adipocytes where it modulates the expression of a program of genes involved in adipocyte function (1). These include genes involved in TGD and fatty acid metabolism and in the expression of adipokines. Adipocyte lipid metabolism and the secretion of adipokines have a powerful effect on systemic substrate utilization and on overall organismal energy metabolism (2, 3). TZD drugs, currently in clinical use for treatment of human diabetes, are established ligands of adipocyte PPAR␥ receptors, and we have previously shown that adipocyte apoE expression is responsive to treatment with these drugs (4). Zechner and colleagues first described expression of apoE by adipocytes in 1991 (5), but only recently has additional information been provided regarding regulation and function of adipocyte apoE (6 -10). Treating isolated adipocytes or intact humans with PPAR␥ agonists increases adipocyte and adipose tissue apoE gene expression (4, 6). The proinflammatory cytokine, tumor necrosis factor-␣, reduces adipocyte apoE expression, an effect mediated by the NF-B transcriptional complex binding an element in the apoE gene proximal promoter (4, 7). Reactive oxygen species produced by the stromovascular fracti...

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