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

## TL;DR

Activin E deficiency in mice leads to a lean-type fatty liver disease despite protection from obesity.

## Contribution

Identifies Activin E as a key regulator in liver and adipose tissue communication and introduces a novel lean-type MASH mouse model.

## Key findings

- Activin E-KO mice on a high-fat diet develop MASH-like liver features without obesity.
- Loss of Activin E causes reduced white adipose tissue and insulin resistance.
- Female Activin E-KO mice show delayed MASH onset, suggesting estrogen-related protection.

## Abstract

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.

•Activin E-KO mice on an HFD show liver enlargement and MASH-like features.•Activin E-KO mice have less WAT fat and impaired insulin sensitivity.•Female KO mice show milder liver damage than male KO mice.•Activin E-KO mice are a lean-type MASH model.

Activin E-KO mice on an HFD show liver enlargement and MASH-like features.

Activin E-KO mice have less WAT fat and impaired insulin sensitivity.

Female KO mice show milder liver damage than male KO mice.

Activin E-KO mice are a lean-type MASH model.