Disrupting the PNPLA3-ABHD5 Interaction Stimulates Lipolysis and Improves PNPLA3-I148M-Associated Hepatic Steatosis.

We evaluate the importance of the protein-protein interaction (PPI) between PNPLA3-I148M and its cofactor α/β-hydrolase domain-containing protein 5 (ABHD5) in PNPLA3-I148M-mediated hepatic steatosis. We demonstrate that disrupting the PNPLA3-ABHD5 PPI improves I148M-associated steatosis and markers of liver injury. This work supports the development of therapies targeting the PNPLA3-ABHD5 PPI for the treatment of PNPLA3-I148M-associated metabolic dysfunction-associated steatotic liver disease.