To Be or Not to Be: The Quest for Patatin-Like Phospholipase Domain Containing 3 p.I148M Function

Understanding the mechanisms underpinning the association between rs738409 C>G encoding for the common p.I148M variant of patatin-like phospholipase domain-containing 3 (PNPLA3) with fat accumulation in hepatocytes may hold the key to unravel new treatments for liver disease. The I148M variant is the main inherited determinant of both nonalcoholic and alcoholic fatty liver disease, now the leading cause of liver related mortality. Furthermore, the p.I148M genotype accounts for a large fraction of the interethnic and interindividual susceptibility to hepatic fat accumulation, and for as much as 16 and 27% of cirrhosis and hepatocellular carcinoma variability in the European population1,2 . Indeed, after the variant identification as the main inherited determinant of liver fat3 , it was shown to translate into increased risk of fibrosis, hepatocellular carcinoma, and liver related mortality in clinical and then in population-based cohorts1,4 . Therefore, correction of the molecular pathway underlying the phenotypic expression this causal factor may represent a next step to reduce the burden of liver disease, after the successes in the prevention and treatment of viral hepatitis.