Retinoic acid-related orphan receptor α regulates diurnal rhythm and fasting induction of sterol 12α-hydroxylase in bile acid synthesis.
Sterol 12α-hydroxylase (CYP8B1) is required for cholic acid synthesis and plays a critical role in intestinal cholesterol absorption and pathogenesis of cholesterol gallstone, dyslipidemia, and diabetes. In this study we investigated the underlying mechanism of fasting induction and circadian rhythm of CYP8B1 by a cholesterol-activated nuclear receptor and core clock gene retinoic acid-related orphan receptor α (RORα). Fasting stimulated, whereas restricted-feeding reduced expression of CYP8B1 mRNA and protein. However, fasting and feeding had little effect on the diurnal rhythm of RORα mRNA expression, but fasting increased RORα protein levels by cAMP-activated protein kinase A-mediated phosphorylation and stabilization of the protein. Adenovirus-mediated gene transduction of RORα to mice strongly induced CYP8B1 expression, and increased liver cholesterol and 12α-hydroxylated bile acids in the bile acid pool and serum. A reporter assay identified a functional RORα response element in the CYP8B1 promoter. RORα recruited cAMP response element-binding protein-binding protein (CBP) to stimulate histone acetylation on the CYP8B1 gene promoter. In conclusion, RORα is a key regulator of diurnal rhythm and fasting induction of CYP8B1, which regulates bile acid composition and serum and liver cholesterol levels. Antagonizing RORα activity may be a therapeutic strategy for treating inflammatory diseases such as non-alcoholic fatty liver disease and type 2 diabetes.
From the Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272 and.
Preeti
P
Pathak
Tiangang
T
Li
John Y L
JY
Chiang
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004790:Enzyme Induction / Q000502:physiology; D005215:Fasting / Q000378:metabolism*; D005234:Fatty Liver / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D013253:Steroid 12-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics
D001647:Bile Acids and Salts; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; C539739:Rora protein, mouse; D002784:Cholesterol; D013253:Steroid 12-alpha-Hydroxylase; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases
Cholesterol; Diabetes; Lipid Metabolism; Nuclear Receptors; Obesity