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Kim YD, Hwang SL, Lee EJ, et al. Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. J Pineal Res. 2017;62(2)doi: 10.1111/jpi.12386.
Kim, Y. D., Hwang, S. L., Lee, E. J., Kim, H. M., Chung, M. J., Elfadl, A. K., Lee, S. E., Nedumaran, B., Harris, R. A., & Jeong, K. S. (2017). Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. Journal of pineal research, 62(2), . https://doi.org/10.1111/jpi.12386
Kim, Yong Deuk, et al. "Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression." Journal of pineal research vol. 62,2 (2017). doi: https://doi.org/10.1111/jpi.12386
Kim YD, Hwang SL, Lee EJ, Kim HM, Chung MJ, Elfadl AK, Lee SE, Nedumaran B, Harris RA, Jeong KS. Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. J Pineal Res. 2017 Mar;62(2). doi: 10.1111/jpi.12386. Epub 2017 Feb 10. PMID: 28095641.
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J Pineal Res. 2017 Mar;62(2). doi: 10.1111/jpi.12386. Epub 2017 Feb 10.

Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression.

Journal of pineal research

Yong Deuk Kim, Seung-Lark Hwang, Eun-Joo Lee, Hyeong-Mi Kim, Myung-Jin Chung, Ahmed K Elfadl, Sung-Eun Lee, Balachandar Nedumaran, Robert A Harris, Kyu-Shik Jeong

Affiliations

  1. Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.
  2. Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea.
  3. School of Applied Biosciences, Kyungpook National University, Daegu, Korea.
  4. Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  5. Roudebush VA Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

PMID: 28095641 DOI: 10.1111/jpi.12386

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.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Keywords: B-cell translocation gene 2; alcohol; bile acid; cholesterol 7α-hydroxylase; microRNA; yin yang 1

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