Activation of cholangiocyte mTORC1 drives alcohol-induced ductular reaction

Alcohol consumption has increased over the COVID-19 pandemic, and this rise in alcohol consumption has led to increases in alcohol-associated liver disease (ALD), and alcoholassociated hepatitis (AH) in particular(1).The growing problem of AH has been exacerbated by the lack of suitable therapeutics to reverse AH, with many patients requiring liver transplants.The etiology of AH is complex, and current animal models of AH have not been able to replicate certain hallmarks of severe AH (sAH) that correlate with prognosis, including ductular reaction (DR).This has greatly limited AH therapeutic development even though many targets and pathways have shown promise in preclinical models.In fact, several studies have shown that mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, energy metabolism, and autophagy, is activated in AH and inhibition of mTORC1 can reverse ethanol-induced liver injury(2).However, the effect of mTORC1 on alcohol-associated DR and its associated liver injury remains unknown.Some of the questions surrounding mTORC1 in ALD are answered in this issue of Hepatology by Chao et al.(3).Chao et al detected increased mTORC1 activation in chronicplus-binge ethanol fed mouse and human AH liver samples, and such elevated mTORC1 activation is associated with decreased protein levels of tuberous sclerosis complex 1 (TSC1), a negative regulator of mTORC1.These findings led the authors to characterize ethanol-induced liver injury in liver specific Tsc1 knockout (L-Tsc1 KO) mice that exhibit constitutive mTORC1 activation.ALT levels were not different between wild-type (WT) and L-Tsc1 KO mice subjected to the control diet, indicating that baseline liver injury may not be different.However, L-Tsc1 KO mice on the control diet exhibited increased liver size, DR, fibrosis, and immune cell infiltration compared to their WT counterparts.Ethanol feeding exacerbated many of these characteristics in the L-Tsc1 KO mice compared to WT, which resembled the human AH phenotype, indicating that the L-Tsc1 KO mice may be predisposed to increased liver injury due to ethanol.The most striking finding was that the DR in the ethanol-fed L-Tsc1 KO mice reproduced the DR found in human AH patients.Since the chronic-binge model of ethanol feeding induces very little DR in WT mice, the DR