Identification of a Metabolic, Transcriptomic, and Molecular Signature of Patatin‐Like Phospholipase Domain Containing 3–Mediated Acceleration of Steatohepatitis

Background and Aims The mechanisms by which the I148M mutant variant of the patatin‐like phospholipase domain‐containing 3 (PNPLA3I148M) drives development of nonalcoholic steatohepatitis (NASH) are not known. The aim of this study was to obtain insights on mechanisms underlying PNPLA3I148M‐induced acceleration of NASH. Approach and Results Hepatocyte‐specific overexpression of empty vector (luciferase), human wild‐type PNPLA3, or PNPLA3I148M was achieved using adeno‐associated virus 8 in a diet‐induced mouse model of nonalcoholic fatty liver disease followed by chow diet or high‐fat Western diet with ad libitum administration of sugar in drinking water (WDSW) for 8 weeks. Under WDSW, PNPLA3I148M overexpression accelerated steatohepatitis with increased steatosis, inflammation ballooning, and fibrosis (P