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<a href="http://doi.org/10.1074/jbc.M113.485987" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.M113.485987</a>
Pages
37154–37165
Issue
52
Volume
288
Dublin Core
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Title
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Retinoic acid-related orphan receptor alpha regulates diurnal rhythm and fasting induction of sterol 12alpha-hydroxylase in bile acid synthesis.
Publisher
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The Journal of biological chemistry
Date
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2013
2013-12
Subject
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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
Creator
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Pathak Preeti; Li Tiangang; Chiang John Y L
Description
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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.
Identifier
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<a href="http://doi.org/10.1074/jbc.M113.485987" target="_blank" rel="noreferrer noopener">10.1074/jbc.M113.485987</a>
Rights
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2013
Animals
Bile Acids and Salts/*biosynthesis
Chiang John Y L
Cholesterol
Cholesterol/*biosynthesis/genetics
Circadian Rhythm/*physiology
Department of Integrative Medical Sciences
Diabetes
Diabetes Mellitus
Enzyme Induction/physiology
Fasting/*metabolism
Fatty Liver/drug therapy/genetics/metabolism/pathology
Group F
Hep G2 Cells
Humans
Li Tiangang
Lipid Metabolism
Member 1/genetics/*metabolism
Mice
NEOMED College of Medicine
Non-alcoholic Fatty Liver Disease
Nuclear Receptor Subfamily 1
Nuclear Receptors
Obesity
Pathak Preeti
Phosphorylation/physiology
Protein Kinases/genetics/metabolism
Response Elements/physiology
Steroid 12-alpha-Hydroxylase/*biosynthesis/genetics
The Journal of biological chemistry
Type 2/drug therapy/genetics/metabolism/pathology