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

JOURNAL OF HEPATOLOGY

卷:66

Article

Ramirez, Teresa¹  Li, Yong-Mei¹  Yin, Shi^1,3  Xu, Ming-Jiang¹  Feng, Dechun¹  Zhou, Zhou¹  Zang, Mengwei⁴  Mukhopadhyay, Partha⁵  Varga, Zoltan V.⁵  Pacher, Pal⁵  Gao, Bin¹  Wang, Hua^1,2 

[1] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA

[2] Anhui Med Univ, Inst Liver Dis, Affiliated Hosp 1, Dept Oncol, 218 Jixi Rd, Hefei 230032, Peoples R China

[3] Anhui Med Univ, Affiliated Prov Hosp, Dept Geriatr, Hefei 230032, Peoples R China

[4] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Dept Mol Med, San Antonio, TX 78229 USA

[5] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD 20892 USA

关键词: Fatty liver;    Steatohepatitis;    Ethanol;    PDGFR-alpha;    Middle-age;    Hepatic stellate cells (HSCs);   

DOI  :  10.1016/j.jhep.2016.11.004

来源: Elsevier

【 摘 要 】

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-alpha 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-alpha expression. Conclusions: Aging exacerbates ALD in mice through the down regulation 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. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

【 授权许可】

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