Retinoic acid-related orphan receptor alpha regulates diurnal rhythm and fasting induction of sterol 12alpha-hydroxylase in bile acid synthesis.

Retinoic acid-related orphan receptor alpha regulates diurnal rhythm and fasting induction of sterol 12alpha-hydroxylase in bile acid synthesis.

Pathak Preeti; Li Tiangang; Chiang John Y L

The Journal of biological chemistry

2013

2013-12

Sterol 12alpha-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 alpha (RORalpha). Fasting stimulated, whereas restricted-feeding reduced expression of CYP8B1 mRNA and protein. However, fasting and feeding had little effect on the diurnal rhythm of RORalpha mRNA expression, but fasting increased RORalpha protein levels by cAMP-activated protein kinase A-mediated phosphorylation and stabilization of the protein. Adenovirus-mediated gene transduction of RORalpha to mice strongly induced CYP8B1 expression, and increased liver cholesterol and 12alpha-hydroxylated bile acids in the bile acid pool and serum. A reporter assay identified a functional RORalpha response element in the CYP8B1 promoter. RORalpha recruited cAMP response element-binding protein-binding protein (CBP) to stimulate histone acetylation on the CYP8B1 gene promoter. In conclusion, RORalpha is a key regulator of diurnal rhythm and fasting induction of CYP8B1, which regulates bile acid composition and serum and liver cholesterol levels. Antagonizing RORalpha activity may be a therapeutic strategy for treating inflammatory diseases such as non-alcoholic fatty liver disease and type 2 diabetes.

Animals; Bile Acids and Salts/*biosynthesis; Cholesterol; Cholesterol/*biosynthesis/genetics; Circadian Rhythm/*physiology; Diabetes; Diabetes Mellitus; Enzyme Induction/physiology; Fasting/*metabolism; Fatty Liver/drug therapy/genetics/metabolism/pathology; Group F; Hep G2 Cells; Humans; Lipid Metabolism; Member 1/genetics/*metabolism; Mice; Non-alcoholic Fatty Liver Disease; Nuclear Receptor Subfamily 1; Nuclear Receptors; Obesity; Phosphorylation/physiology; Protein Kinases/genetics/metabolism; Response Elements/physiology; Steroid 12-alpha-Hydroxylase/*biosynthesis/genetics; Type 2/drug therapy/genetics/metabolism/pathology

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