Peroxisome proliferator-activated receptor-gamma coactivator-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by small heterodimer partner.
Cholesterol 7alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of hepatic bile acid biosynthesis from cholesterol. During fasting and in type I diabetes, elevated levels of peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) induce expression of the Cyp7A1 gene and overexpression of PGC-1alpha in hepatoma cells stimulates bile acid synthesis. Using Ad-PGC-1alpha-RNA interference to induce acute disruption of PGC-1alpha in mice, here we show that PGC-1alpha is necessary for fasting-mediated induction of CYP7A1. Co-immunoprecipitation and promoter activation studies reveal that the induction of CYP7A1 is mediated by direct interaction between PGC-1alpha and the AF2 domain of liver receptor homolog-1 (LRH-1). In contrast, the very similar PGC-1beta could not substitute for PGC-1alpha. We also show that transactivation of PGC-1alpha and LRH-1 is repressed by the small heterodimer partner (SHP). Treatment of mice with GW4064, a synthetic agonist for farnesoid X receptor, induced SHP expression and decreased both the recruitment of PGC-1alpha to the Cyp7A1 promoter and the fasting-induced expression of CYP7A1 mRNA. These data suggest that PGC-1alpha is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1alpha to inhibit CYP7A1 expression. Overall, these studies provide further evidence for the important role of PGC-1alpha in bile acid homeostasis and suggest that pharmacological targeting of farnesoid X receptor in vivo can be used to reverse the increase in CYP7A1 associated with adverse metabolic conditions.
Shin
Dong-Ju
DJ
Department of Molecular Biology and Biochemistry, School of Biological Sciences, Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697-3900, USA.
Osborne
Timothy F
TF
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005215:Fasting / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007555:Isoxazoles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C082631:NR5A2 protein, human; C431936:Nr5a2 protein, mouse; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; C485290:Ppargc1a protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C502772:Cyp7a1 protein, mouse; C412815:GW 4064