The Patatin-Like Phospholipase Domain-Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice.

Patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC); however, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3^148M variant in alcohol-related HCC development. Control and humanized PNPLA3^148M transgenic mice were fed with an ethanol-containing diet for 12 weeks. The animals were examined for liver tumors. After the alcohol feeding, the PNPLA3^148M mice had twofold higher liver cancer incidence rates and larger tumor sizes than those in the control mice. Cancer stem cell markers in the PNPLA3^148M mouse livers were elevated relative to those in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3^148M mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3^148M mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (TAZ) were activated in the PNPLA3^148M mouse livers. The data suggest that the PNPLA3^148M variant has a strong interaction with alcohol in HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3^148M variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.