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

Area of Science:

• Hepatology
• Metabolic Diseases
• Cellular Senescence

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are major causes of chronic liver disease, cirrhosis, and liver cancer.
• These conditions are linked to increased senescence proteins, such as Activin A, and senolytics are being explored as treatments.

Purpose of the Study:

• To investigate the role of hepatic Activin A in a mouse model of MASLD/MASH.
• To explore the potential of senescence-associated secretory phenotype (SASP) proteins as therapeutic targets.

Main Methods:

• Hepatic expression of Activin A was induced in a murine MASLD/MASH model.
• The study analyzed liver steatosis, inflammation, systemic fat accumulation, and insulin sensitivity.
• The expression of glycoprotein NMB (Gpnmb), a marker for lipid-associated macrophages, was investigated in relation to Activin A.

Main Results:

• Overexpression of hepatic Activin A significantly reduced liver steatosis, inflammation, and systemic fat accumulation.
• Activin A improved insulin sensitivity in the MASLD/MASH model.
• Activin A decreased Gpnmb expression, and Gpnmb knockdown mimicked the beneficial effects of Activin A.

Conclusions:

• Activin A exhibits a protective role in MASLD, contrary to expectations.
• SASP proteins can have context-specific beneficial effects.
• Activin A and Gpnmb are identified as potential therapeutic targets for MASLD.