Roles of Activin A and Gpnmb in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Huan Liu, Armen Yerevanian, Maria Westerhoff, Margaret H. Hastings, Justin Ralph Baldovino Guerra, Meng Zhao, Katrin J. Svensson, Bishuang Cai, Alexander A. Soukas, Anthony Rosenzweig

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 lipidassociatedmacrophagesmarker glycoprotein NMB (Gpnmb) by Activin A, and Gpnmb knockdown in the samemodel 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.

Original languageEnglish
Pages (from-to)260-279
Number of pages20
JournalDiabetes
Volume73
Issue number2
DOIs
StatePublished - Feb 2024

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