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Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced Adipose Atrophy and Liver Injury.

ABSTRACT: Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver injury remain unclear. To determine the role of adipose autophagy and mechanistic target of rapamycin (mTOR) in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (KO), adipocyte-specific mTOR KO, adipocyte-specific Raptor KO, and adipocyte-specific tuberous sclerosis complex 1 KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type mice were challenged with chronic-plus-binge alcohol mouse model. Chronic-plus-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in wild-type mice. Adipocyte-specific Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither adipocyte-specific mTOR nor adipocyte-specific tuberous sclerosis complex 1 KO mice exhibited similar detrimental effects. Adipocyte-specific Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 and adiponectin and were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.

PROVIDER: S-EPMC6940593 | BioStudies |

REPOSITORIES: biostudies

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