Fatty liver—too much of a bad thing?

Metabolic Disease Human genetic studies have been instrumental for developing drugs that prevent cardiometabolic disease. Key examples are statins and anti-body-based therapies that lower serum levels of low-density lipoprotein (LDL) cholesterol. A similar paradigm may apply to fatty liver disease, an increasingly prevalent disorder that can progress to cirrhosis. Fatty liver is more common in individuals carrying a certain variant of the gene PNPLA3 (patatin-like phospholipase domain-containing protein 3) that leads to accumulation of the protein on lipid droplets in the liver. Whether this aberrant accumulation causes the disease was unknown. BasuRay et al. show that removing PNPLA3 from the liver by targeted protein degradation or by RNA interference ameliorates fatty liver in mice and may be a suitable target for therapeutic interventions. Proc. Natl. Acad. Sci. U.S.A. 116 , 9521 (2019).