Yes-associated
protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self-renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis,
hepatitis, and
cirrhosis. Accumulation of this
protein in the nucleus was also observed in murine livers that were damaged after chronic-plus-single binge or moderate
ethanol ingestion combined with
carbon tetrachloride intoxication (
ethanol/CCl4 ). To understand the role of this transcriptional coactivator in alcohol-related liver injury, we knocked out the Yap1 gene in hepatocytes of floxed homozygotes through adeno-associated virus (AAV8)-mediated deletion utilizing
Cre recombinase. Yap1 hepatocyte-specific knockouts (KO) exhibited
hemorrhage,
massive hepatic necrosis, enhanced oxidative stress, elevated
hypoxia, and extensive infiltration of CD11b+ inflammatory cells into hepatic microenvironments rich for
connective tissue growth factor (Ctgf) during
ethanol/CCl4 -induced liver damage. Analysis of whole-genome transcriptomics indicated upregulation of genes involved in
hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and
ethanol detoxification were downregulated in the damaged livers of Yap1 KO.
Acetaldehyde dehydrogenase (Aldh)1a1, a gene that encodes a detoxification
enzyme for
aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human ALDH1A1 gene caused increase in hepatocyte proliferation and decrease in hepatic
necrosis, oxidative stress, ECM remodeling, and
inflammation during
ethanol/CCl4 -induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol-associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification.