title: Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression.
abstract: Alcoholic liver disease is a major cause of chronic liver disease worldwide, and cannabinoid receptor type 1 (CB1R) is involved in a diverse metabolic diseases. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are a potent regulator of biological conditions. Melatonin plays a crucial role in regulating diverse physiological functions and metabolic homeostasis. MicroRNAs are key regulators of various biological processes. Herein, we demonstrate that melatonin improves bile acid synthesis in the liver of alcohol-fed mice by controlling miR-497 expression. The level of bile acid and the expression of Cb1r, Btg2, Yy1, and bile acid synthetic enzymes were significantly elevated in the livers of Lieber-DeCarli alcohol-fed mice. The overexpression of Btg2 enhanced Yy1 gene expression and bile acid production, whereas disrupting the CB1R-BTG2-YY1 cascade protected against the bile acid synthesis caused by alcohol challenge. We identified an alcohol-mediated YY1 binding site on the cholesterol 7α-hydroxylase (Cyp7a1) gene promoter using promoter deletion analysis and chromatin immunoprecipitation assays. Notably, melatonin attenuated the alcohol-stimulated induction of Btg2, Yy1 mRNA levels and bile acid production by promoting miR-497. Overexpression of a miR-497 mimic dramatically diminished the increase of Btg2 and Yy1 gene expression as well as bile acid production by alcohol, whereas this phenomenon was reversed by miR-497 inhibitor. These results demonstrate that the upregulation of miR-497 by melatonin represses alcohol-induced bile acid synthesis by attenuating the BTG2-YY1 signaling pathway. The melatonin-miR497 signaling network may provide novel therapeutic targets for the treatment of hepatic metabolic dysfunction caused by the alcohol-dependent pathway.
authors.affiliation: Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.|Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.|School of Applied Biosciences, Kyungpook National University, Daegu, Korea.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: School of Applied Biosciences, Kyungpook National University, Daegu, Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.affiliation: Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.|Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.|Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Hyeong-Mi
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.|Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Chung
authors.affiliation: Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.|Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Ahmed K
authors.initials: AK
authors.lastname: Elfadl
authors.affiliation: School of Applied Biosciences, Kyungpook National University, Daegu, Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Balachandar
authors.initials: B
authors.lastname: Nedumaran
authors.affiliation: Roudebush VA Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.|Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Kyu-Shik
authors.identifier: http://orcid.org/0000-0003-1725-638X
authors.initials: KS
authors.lastname: Jeong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis*; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051758:Transcription Factor TFIIH / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001647:Bile Acids and Salts; D035683:MicroRNAs; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; C550139:mirn497 microRNA, mouse; D051758:Transcription Factor TFIIH; D008550:Melatonin
keywords: B-cell translocation gene 2; alcohol; bile acid; cholesterol 7α-hydroxylase; microRNA; yin yang 1