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Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury.

Authors
  • Wan, Ying1
  • McDaniel, Kelly2
  • Wu, Nan3
  • Ramos-Lorenzo, Sugeily4
  • Glaser, Trenton4
  • Venter, Julie3
  • Francis, Heather2
  • Kennedy, Lindsey5
  • Sato, Keisaku3
  • Zhou, Tianhao5
  • Kyritsi, Konstantina3
  • Huang, Qiaobing6
  • Annable, Tami7
  • Wu, Chaodong8
  • Glaser, Shannon2
  • Alpini, Gianfranco9
  • Meng, Fanyin10
  • 1 Division of Research, Central Texas Veterans Healthcare System, Temple, Texas; Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, Texas; Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Temple, Texas; Department of Pathophysiology, Southwest Medical University, Luzhou, China. , (China)
  • 2 Division of Research, Central Texas Veterans Healthcare System, Temple, Texas; Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, Texas; Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Temple, Texas.
  • 3 Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Temple, Texas.
  • 4 Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, Texas.
  • 5 Division of Research, Central Texas Veterans Healthcare System, Temple, Texas; Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Temple, Texas.
  • 6 Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, China. , (China)
  • 7 Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, Texas; Temple Health and Bioscience District, Temple, Texas.
  • 8 Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
  • 9 Division of Research, Central Texas Veterans Healthcare System, Temple, Texas; Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, Texas; Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Temple, Texas. Electronic address: [email protected]
  • 10 Division of Research, Central Texas Veterans Healthcare System, Temple, Texas; Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, Texas; Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Temple, Texas. Electronic address: [email protected]
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Dec 01, 2017
Volume
187
Issue
12
Pages
2788–2798
Identifiers
DOI: 10.1016/j.ajpath.2017.08.027
PMID: 29128099
Source
Medline
License
Unknown

Abstract

Alcoholic liver disease remains a major cause of liver-related morbidity and mortality, which ranges from alcoholic steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma, and the related mechanisms are understood poorly. In this study, we aimed to investigate the role of miR-34a in alcohol-induced cellular senescence and liver fibrosis. We found that hepatic miR-34a expression was upregulated in ethanol-fed mice and heavy drinkers with steatohepatitis compared with respective controls. Mice treated with miR-34a Vivo-Morpholino developed less severe liver fibrosis than wild-type mice after 5 weeks of ethanol feeding. Further mechanism exploration showed that inhibition of miR-34a increased cellular senescence of hepatic stellate cells (HSCs) in ethanol-fed mice, although it decreased senescence in total liver and hepatocytes, which was verified by the changes of senescence-associated β-galactosidase and gene expression. Furthermore, enhanced cellular senescence was observed in liver tissues from steatohepatitis patients compared with healthy controls. In addition, the expression of transforming growth factor-β1, drosophila mothers against decapentaplegic protein 2 (Smad2), and Smad3 was decreased after inhibition of miR-34a in ethanol-fed mice. Our in vitro experiments showed that silencing of miR-34a partially blocked activation of HSCs by lipopolysaccharide and enhanced senescence of HSCs. Furthermore, inhibition of miR-34a decreased lipopolysaccharide-induced fibrotic gene expression in cultured hepatocytes. In conclusion, our data suggest that miR-34a functions as a profibrotic factor that promotes alcohol-induced liver fibrosis by reducing HSC senescence and increasing the senescence of hepatocytes.

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