title: Peroxisome proliferator-activated receptor {gamma} stimulation of adipocyte ApoE gene transcription mediated by the liver receptor X pathway.
abstract: 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.
authors.affiliation: Departments of Medicine, Pharmacology, and Human Nutrition, University of Illinois, Chicago, Illinois 60612.
authors.forename: Lili
authors.initials: L
authors.lastname: Yue
authors.forename: Theodore
authors.initials: T
authors.lastname: Mazzone
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014280:Triglycerides; C039671:ciglitazone