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

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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere12386
JournalJournal of Pineal Research
Volume62
Issue number2
DOIs
StatePublished - Mar 1 2017

Fingerprint

Melatonin
Bile Acids and Salts
Alcohols
Yin-Yang
B-Lymphocytes
Genes
Liver
Cholesterol 7-alpha-Hydroxylase
Biological Phenomena
Gene Expression
Cannabinoid Receptors
Alcoholic Liver Diseases
Chromatin Immunoprecipitation
Metabolic Diseases
MicroRNAs
Liver Diseases
Homeostasis
Chronic Disease
Up-Regulation
Binding Sites

Keywords

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

ASJC Scopus subject areas

  • Endocrinology

Cite this

Kim, Y. D., Hwang, S. L., Lee, E. J., Kim, H. M., Chung, M. J., Elfadl, A. K., ... Jeong, K. S. (2017). Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. Journal of Pineal Research, 62(2), [e12386]. https://doi.org/10.1111/jpi.12386

Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. / Kim, Yong Deuk; Hwang, Seung Lark; Lee, Eun Joo; Kim, Hyeong Mi; Chung, Myung Jin; Elfadl, Ahmed K.; Lee, Sung Eun; Nedumaran, Balachandar; Harris, Robert; Jeong, Kyu Shik.

In: Journal of Pineal Research, Vol. 62, No. 2, e12386, 01.03.2017.

Research output: Contribution to journalArticle

Kim, YD, Hwang, SL, Lee, EJ, Kim, HM, Chung, MJ, Elfadl, AK, Lee, SE, Nedumaran, B, Harris, R & Jeong, KS 2017, 'Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression', Journal of Pineal Research, vol. 62, no. 2, e12386. https://doi.org/10.1111/jpi.12386
Kim, Yong Deuk ; Hwang, Seung Lark ; Lee, Eun Joo ; Kim, Hyeong Mi ; Chung, Myung Jin ; Elfadl, Ahmed K. ; Lee, Sung Eun ; Nedumaran, Balachandar ; Harris, Robert ; Jeong, Kyu Shik. / Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. In: Journal of Pineal Research. 2017 ; Vol. 62, No. 2.
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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.",
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