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OBJECTIVE The aim of the study is to investigate the role and mechanisms of tuberous sclerosis complex 1 (TSC1) and mechanistic target of rapamycin complex 1 (mTORC1) in alcohol associated liver disease. DESIGN Liver-specific Tsc1 knockout (L-Tsc1 KO) mice and their matched wild type ( WT) mice were subjected to Gao-binge alcohol. Human alcoholic hepatitis (AH) samples were also used for immunohistochemical (IHC) staining, western blot and q-PCR analysis. RESULTS Human AH and Gao-binge alcohol-fed mice had decreased hepatic TSC1 and increased mTORC1 activation. Gao-binge alcohol markedly increased liver/body weight ratio and serum alanine aminotransferase (ALT) levels in L-Tsc1 KO mice compared to Gao-binge alcohol-fed WT mice. Results from IHC staining, western blot and q-PCR analysis revealed that human AH and Gao-binge alcohol-fed L-Tsc1 KO mouse livers significantly increased hepatic progenitor cells, macrophages and neutrophils but decreased HNF4α positive cells. Gao-binge alcohol-fed L-Tsc1 KO mice also developed severe inflammation and liver fibrosis. Deleting Tsc1 in cholangiocytes but not in hepatocytes promoted cholangiocyte proliferation and aggravated alcohol-induced ductular reactions (DR), fibrosis, inflammation and liver injury. Pharmacological inhibition of mTORC1 partially reversed hepatomegaly, DR, fibrosis, inflammatory cell infiltration and liver injury in alcohol-fed L-Tsc1 KO mice. CONCLUSION Our findings indicate that persistent activation of mTORC1 due to the loss of cholangiocyte TSC1 promotes hepatomegaly, liver cell repopulation, DR, inflammation, fibrosis and liver injury in Gao-binge alcohol fed L-Tsc1 KO mice, which phenocopy the pathogenesis of human AH.