Author information
1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
2Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, MI.
3Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
4Department of Pathology, University of Michigan, Ann Arbor, MI.
5Department of Pathology, Stanford University School of Medicine, Stanford, CA.
6Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA.
7Stanford Cardiovascular Institute, Stanford University School of Medicine, CA.
8Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease [NAFLD]) and metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]) are leading chronic liver diseases, driving cirrhosis, hepatocellular carcinoma, and mortality. MASLD/MASH is associated with increased senescence proteins, including Activin A, and senolytics have been proposed as a therapeutic approach. To test the role of Activin A, we induced hepatic expression of Activin A in a murine MASLD/MASH model. Surprisingly, overexpression of hepatic Activin A dramatically mitigated MASLD, reducing liver steatosis and inflammation as well as systemic fat accumulation, while improving insulin sensitivity. Further studies identified a dramatic decrease in the lipid-associated macrophages marker glycoprotein NMB (Gpnmb) by Activin A, and Gpnmb knockdown in the same model produced similar benefits and transcriptional changes to Activin A expression. These studies reveal a surprising protective role for Activin A in MASLD and the potential for SASP proteins to have context-specific beneficial effects. Moreover, they implicate both Activin A and Gpnmb as potential therapeutic targets for this condition.