Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Teresa Ramirez, Yong Mei Li, Shi Yin, Ming Jiang Xu, Dechun Feng, Zhou Zhou, Mengwei Zang, Partha Mukhopadhyay, Zoltan V. Varga, Pal Pacher, Bin Gao, Hua Wang

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background & Aims Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. The aim of this study was to use a chronic plus binge ethanol feeding model in mice to evaluate the effects of aging on alcohol-induced liver injury. Methods C57BL/6 mice were subjected to short-term (10 days) ethanol plus one binge or long-term (8 weeks) ethanol plus multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results Middle-aged (12–14 months) and old-aged (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term plus one binge or long-term plus multiple binges of ethanol feeding when compared to young (8–12 weeks) mice. Long-term plus multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term plus binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to long-term chronic-plus-multiple binges of ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. Conclusions Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD. Lay summary Aged mice are more susceptible to alcohol-induced liver injury and fibrosis, which is, at least in part, due to lower levels of sirtuin 1 protein in hepatocytes and hepatic stellate cells. Our findings suggest that sirtuin 1 activators may have beneficial effects for the treatment of alcoholic liver disease in aged patients.

Original languageEnglish (US)
Pages (from-to)601-609
Number of pages9
JournalJournal of Hepatology
Volume66
Issue number3
DOIs
StatePublished - Mar 1 2017

Keywords

  • Ethanol
  • Fatty liver
  • Hepatic stellate cells (HSCs)
  • Middle-age
  • PDGFR-α
  • Steatohepatitis

ASJC Scopus subject areas

  • Hepatology

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