title: Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression.
abstract: 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.
  
  
  
  C57BL/6 mice were subjected to short-term (10days) ethanol plus one binge or long-term (8weeks) ethanol plus multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies.
  
  
  
  Middle-aged (12-14months) and old-aged (>16months) 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 (8-12weeks) 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramirez
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Li
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA; Department of Geriatrics, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230032, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Yin
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA.
authors.forename: Dechun
authors.initials: D
authors.lastname: Feng
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Barshop Institute for Longevity and Aging Studies, Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX 78229, USA.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD 20892, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD 20892, USA.
authors.forename: Zoltan V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD 20892, USA.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA. Electronic address: bgao@mail.nih.gov.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD 20892, USA; Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei 230032, China. Electronic address: wanghua@ahmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D063425:Binge Drinking; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics*
chemical_list: C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Ethanol; Fatty liver; Hepatic stellate cells (HSCs); Middle-age; PDGFR-α; Steatohepatitis