Alcohol consumption and high caloric diet are leading causes of progressive
fatty liver disease. Genetic variant rs738409 in patatin-like
phospholipase domain-containing
protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for
alcoholic liver cirrhosis (ALC) and
hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high
sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after 1 year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic
inflammation or
fibrosis, but induced a striking
lipid remodeling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-
polyunsaturated fatty acids (LC-PUFA)-containing TGs,
docosapentaenoic acid (C22:5 n3) and omega-3-derived
eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated
enzymes for
fatty acid and TG transport and metabolism. These findings suggest (dietary)
lipids as an important and independent driver of hepatic
tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modeling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.