A common polymorphism in PNPLA3 at rs738409 (adiponutrin) gene is associated with a markedly increase liver fat content. This finding has been replicated in at least 20 studies across the world. The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers.