Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis

Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD+-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-indu...

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Published inThe American journal of pathology Vol. 190; no. 1; pp. 82 - 92
Main Authors Zhou, Zhou, Ye, Ting Jie, DeCaro, Elizabeth, Buehler, Brian, Stahl, Zachary, Bonavita, Gregory, Daniels, Michael, You, Min
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.01.2020
American Society for Investigative Pathology
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Summary:Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD+-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion [SIRT1i knockout (KO)] and flox control [wild-type (WT)] mice with a chronic–plus-binge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with inhibition of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for ALD in humans.
ISSN:0002-9440
1525-2191
DOI:10.1016/j.ajpath.2019.09.012