Involvement of Activin E depletion in metabolic dysfunction-associated steatohepatitis.

Activin E is a liver-derived hepatokine belonging to the transforming growth factor-β superfamily, and it promotes energy expenditure by activating brown and beige adipocytes. Activin E also possesses anti-lipolytic activity. When Activin E knockout (KO) mice are fed a high-fat diet, energy storage in adipose tissue is impaired, leading to ectopic fat accumulation in the liver. In this study, we investigated the involvement of Activin E depletion in metabolic dysfunction-associated steatohepatitis (MASH), and we characterized the phenotype of Activin E-KO mice under a high-fat diet. Despite being protected from obesity, Activin E-KO mice developed pronounced hepatomegaly, hepatic triglyceride accumulation, and histological features consistent with MASH, including steatosis, ballooning degeneration, fibrosis, and increased hepatic crown-like structures. An RNA sequencing analysis showed a gene expression signature characteristic of MASH, including upregulation of inflammatory and fibrogenic pathways. In contrast, white adipose tissue mass and adipocyte size were markedly reduced, accompanied by elevated circulating non-esterified fatty acid and insulin concentrations, indicating adipose tissue dysfunction and insulin resistance. These features were observed even in the absence of obesity, indicating a lean-type MASH phenotype. Notably, Activin E-KO female mice showed delayed disease onset, suggesting estrogen-related protection. Our findings establish Activin E as a key regulator of adipose-liver metabolic communication and suggest that its loss promotes MASH via impaired lipid storage in white adipose tissue and an increased hepatic lipid burden. High-fat diet-fed Activin E-KO mice represent a novel lean-type MASH model and may serve as a useful platform for investigating hepatokine-targeted therapies.