Altered Catecholamine Stimulated Adipose Lipolysis Contributes to Hepatic Steatosis in Pnpla3I148M Mice

The PNPLA3I148M variant is responsible for the greatest burden of metabolic dysfunction-associated steatotic liver disease (MASLD) among known genetic variants,1 but the underlying mechanism by which the mutant patatin-like phospholipase domain containing 3 (PNPLA3) protein drives disease is incompletely understood. Two mechanisms have been described: (1) the mutant protein sequesters comparative gene identification 58 (CGI58) at the hepatocyte lipid droplet preventing efficient adipose triglyceride lipase (ATGL)-mediated lipid droplet lipolysis2,3; and (2) the efficiency of very low-density lipoprotein (VLDL) production is diminished due to decreased liberation of polyunsaturated fatty acids (PUFAs) for hepatocellular phospholipid synthesis.