Aldehyde Dehydrogenase 2 Deficiency Impairs Liver Progenitor Cell Proliferation in Alcohol-Fed Mice

Abstract

Aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in the detoxification of acetaldehyde. Although numerous studies have demonstrated the significance of ALDH2 in alcohol-associated liver disease, its role in alcohol-induced activation of liver progenitor cells (LPCs) has not been thoroughly investigated. Proteomic analysis of serum samples from patients with either normal ALDH2 genotype or ALDH2 mutation following alcohol consumption revealed that ALDH2 deficiency may suppress LPC proliferation. To test this hypothesis, Aldh2 knockout (Aldh2KO) mice were generated and fed a 3,5-diethoxycarbonyl1,4-dihydrocollidine-supplemented diet along with 10% ethanol in drinking water. A significant inhibition of LPC proliferation was observed in Aldh2KO mice after alcohol exposure, as indicated by reduced numbers of pan-cytokeratin (PanCK)- and Ki-67-positive cells in the liver. Bulk RNA sequencing revealed that differentially expressed genes (DEGs) in 3,5-diethoxycarbonyl1,4-dihydrocollidine plus ethanol-fed Aldh2KO mice were enriched in pathways related to inflammation (up-regulated DEGs) and cell cycle suppression (down-regulated DEGs) based on Reactome pathway analysis compared with wild-type mice. Mechanistically, alcohol exposure in Aldh2KO mice led to reduced LPC proliferation, likely mediated by enhanced hepatic pyroptosis and inflammatory responses. In conclusion, these findings suggest that ALDH2 deficiency appears to impair LPC proliferation in alcohol-associated liver disease, highlighting the critical role of ALDH2 in liver regeneration following alcohol-induced injury.