American Diabetes Association
3 files

Roles of Activin A and Gpnmb in metabolic dysfunction-associated steatotic liver disease (MASLD)

posted on 2023-11-07, 20:55 authored by Huan Liu, Armen Yerevanian, Maria Westerhoff, Margaret H. Hastings, Justin Ralph Baldovino Guerra, Meng Zhao, Katrin J. Svensson, Bishuang Cai8, Alexander A. Soukas, Anthony Rosenzweig

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 (LAM) 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.


American Heart Association 23IPA1042031 23MERIT1038415 postdoctoral fellowship 905674

U.S. Department of Health and Human Services > National Institutes of Health K99AR081618 P30DK040561 P30DK116074 R01AG061034 R01DK125260 R01DK134610 R01HL167107 R35GM147269 R35HL155318