代谢功能障碍相关的脂肪性肝病（MASLD，以前称为非酒精性脂肪性肝病（NAFLD））和代谢功能障碍相关的脂肪性肝炎（MASH，以前称为非酒精性脂肪性肝炎（NASH））是导致慢性肝病的主要原因，导致肝硬化、肝细胞癌和死亡率。 MASLD/MASH 与衰老蛋白（包括激活素 A）增加有关，并且 senolytics 已被提议作为一种治疗方法。为了测试激活素 A 的作用，我们在小鼠 MASLD/MASH 模型中诱导了激活素 A 的肝脏表达。令人惊讶的是，肝激活素 A 的过度表达可显着减轻 MASLD，减少肝脏脂肪变性和炎症以及全身脂肪积累，同时提高胰岛素敏感性。进一步的研究发现，在同一模型中，激活素 A 和 Gpnmb 敲除可显着降低脂质相关巨噬细胞 (LAM) 标记物糖蛋白 NMB (Gpnmb)，从而产生类似的益处以及激活素 A 表达的转录变化。这些研究揭示了激活素 A 在 MASLD 中具有令人惊讶的保护作用，以及 SASP 蛋白具有特定背景有益作用的潜力。此外，他们暗示 Activin A 和 Gpnmb 都是这种情况的潜在治疗靶点。© 2023，美国糖尿病协会。

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.© 2023 by the American Diabetes Association.