Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury.
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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 -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-1, drosophila mothers against decapentaplegic protein 2 (Smad2), and Smad3 was decreased after inhibition of miR-34a in ethanol-fed mice. Our invitro 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.
author list (cited authors)
Wan, Y., McDaniel, K., Wu, N., Ramos-Lorenzo, S., Glaser, T., Venter, J., ... Meng, F.
complete list of authors
Wan, Ying||McDaniel, Kelly||Wu, Nan||Ramos-Lorenzo, Sugeily||Glaser, Trenton||Venter, Julie||Francis, Heather||Kennedy, Lindsey||Sato, Keisaku||Zhou, Tianhao||Kyritsi, Konstantina||Huang, Qiaobing||Annable, Tami||Wu, Chaodong||Glaser, Shannon||Alpini, Gianfranco||Meng, Fanyin