title: Retinoid acid-related orphan receptor γ, RORγ, participates in diurnal transcriptional regulation of lipid metabolic genes.
abstract: The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORγ robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12α-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORγ. The enhanced recruitment of RORγ to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORγ regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of RORγ reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORγ(-/-) mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORγ-deficient mice. Altogether, our study indicates that RORγ functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes.
authors.affiliation: Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.affiliation: Collaborative Mass Spectrometry Group, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Department of Medicine, Colombia University, New York, NY 10032, USA.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Colombia University, New York, NY 10032, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
authors.affiliation: Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA jetten@niehs.nih.gov.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D057906:Circadian Clocks / Q000235:genetics*; D000081031:Fatty Acid Elongases; D005786:Gene Expression Regulation; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020218:Response Elements; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C000630960:Elovl3 protein, mouse; C506120:Insig2 protein, mouse; D008565:Membrane Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D014280:Triglycerides; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases