RRC ID 27881
Author Ni HM, Du K, You M, Ding WX.
Title Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity.
Journal Am J Pathol
Abstract Autophagy is a lysosomal degradation process that degrades long-lived cellular proteins and damaged organelles as a critical cell survival mechanism in response to stress. We recently reported that acute ethanol induces autophagy, which then reduces ethanol-induced liver injury. However, the mechanisms by which ethanol induces autophagy are not known. In the present study, ethanol treatment significantly increased both mRNA and protein levels of various essential autophagy-related genes in primary cultured mouse hepatocytes and in mouse liver. Both nuclear translocation of FoxO3a and expression of FoxO3a target genes were increased in ethanol-treated primary hepatocytes and mouse liver. Overexpression of a dominant negative form of FoxO3a inhibited ethanol-induced autophagy-related gene expression and enhanced ethanol-induced cell death in primary hepatocytes, which suggests that FoxO3a is a key factor in regulating ethanol-induced autophagy and cell survival. Resveratrol, a well-known SIRT1 agonist, further enhanced ethanol-induced expression of autophagy-related genes, likely via increased deacetylation of FoxO3a. Moreover, acute ethanol-treated Foxo3a(-/-) mice exhibited decreased autophagy-related gene expression, but enhanced steatosis and liver injury, compared with wild-type mice. FoxO3a thus plays a critical role in ethanol-induced autophagy in mouse liver. Modulating the FoxO3a autophagy pathway may offer novel therapeutic approaches for treating alcoholic liver pathogenesis.
Volume 183(6)
Pages 1815-1825
Published 2013-12-1
DOI 10.1016/j.ajpath.2013.08.011
PII S0002-9440(13)00596-8
PMID 24095927
PMC PMC4851739
MeSH Animals Autophagy* / drug effects Autophagy* / genetics Central Nervous System Depressants / adverse effects* Central Nervous System Depressants / pharmacology Enzyme Inhibitors / pharmacology Ethanol / adverse effects* Ethanol / pharmacology Fatty Liver* / genetics Fatty Liver* / metabolism Fatty Liver* / pathology Forkhead Box Protein O3 Forkhead Transcription Factors* / genetics Forkhead Transcription Factors* / metabolism Gene Expression Regulation Hepatocytes / metabolism Hepatocytes / pathology Liver / metabolism Liver / pathology Liver Diseases, Alcoholic* / genetics Liver Diseases, Alcoholic* / metabolism Liver Diseases, Alcoholic* / pathology Mice Mice, Knockout Resveratrol Sirtuin 1 / antagonists & inhibitors Sirtuin 1 / genetics Sirtuin 1 / metabolism Stilbenes / pharmacology
IF 3.491
Times Cited 86
Mice RBRC03482