Metabolic and epigenetic abnormalities cause hepatic fibrogenesis in metabolic dysfunction-associated steatohepatitis model mice

Sep 30, 2026

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Study investigates how metabolic and epigenetic abnormalities drive hepatic fibrogenesis in metabolic dysfunction–associated steatohepatitis (MASH) model mice. Using time-series liver transcriptomics, GC–MS and LC–MS metabolomics, the work identifies early inflammation and activated matrix remodeling within 1 week after choline-deficient L-amino acid–defined high-fat diet feeding. Metabolomics shows increased pentose phosphate pathway activity, elevated SAM, higher SAM/SAH ratio, and a positive correlation with hepatic Tgfb1 expression; cycloleucine inhibition suppresses fibrogenic signaling. Findings are reproduced in a Gubra–amylin diet-fed ob/ob model with SAM/SAH changes, fibrosis gene upregulation, and altered H3 histone methylation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

MASLD and progression to MASH

Multi-hit mechanisms and existing models

Methods and Experimental Models

CDAHFD-induced MASH model

Gubra–amylin ob/ob model

RNA-Seq and metabolomic approaches

Results

Early inflammation and matrix remodeling

Pentose phosphate pathway and SAM metabolism

Correlation with Tgfb1 expression

Pharmacologic inhibition via cycloleucine

Replication of epigenetic and fibrotic features

Discussion and Conclusions

RESEARCH ARTICLE Metabolic and epigenetic abnormalities cause hepatic fibrogenesis in metabolic dysfunction–associated steatohepatitis model mice Received for publication, January 15, 2025, and in revised form, November 3, 2025 Published, Papers in Press, November 20, 2025 [https://doi.org/10.1016/j.jbc.2025.1](https://doi.org/10.1016/j.jbc.2025.1)10959 Atsushi Miura 1, Shiori Ikeda2, Yuki Kono2, Keigo Kawate 1, Takashi Hosono 1,2,3,*, and Taiichiro Seki 1,2,3 From the 1Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan; 2Department of Chemistry and Life Science, Nihon University College of Bioresource Sciences, Fujisawa, Kanagawa, Japan; and 3Department of Bioscience, Nihon University College of Bioresource Sciences, Fujisawa, Kanagawa, Japan Reviewed by members of the JBC Editorial Board. Edited by Qi-Qun Tang The prevalence rates of liver-related metabolic syndrome, metabolic dysfunction–associated steatotic liver disease, and the consequent metabolic dysfunction–associated steatohepatitis (MASH) are increasing worldwide. There is a wellestablished and reproducible choline-deficient L-amino acid–defined high-fat diet (CDAHFD)–induced MASH model, but the cause of the hepatic fibrogenesis in this model is unclear. We evaluated the phenotypic changes associated with hepatic fibrogenesis in CDAHFD-fed mice using RNA sequencing, GC–MS, and LC–MS–based metabolic analyses. A time-series liver transcriptomic analysis revealed inflammation and activated matrix remodeling within 1 week in the CDAHFD-fed mouse liver. Also, metabolomic analysis revealed increased activity in the pentose phosphate pathway, an elevated S-adenosylmethionine (SAM) level, and an increased SAM/S-adenosylhomocysteine (SAH) ratio in the CDAHFDfed mouse liver. The increased SAM/SAH ratio positively correlated with hepatic Tgfb1 mRNA expression. Moreover, the SAM synthesis inhibitor cycloleucine suppressed the activation of fibrogenic signaling and subsequent fibrogenesis in the liver. In the Gubra–amylin liver nonalcoholic steatohepatitis diet–fed ob/ob mouse model of MASH, increases in the SAM/ SAH ratio, upregulation of fibrosis-related genes, and alterations in H3 histone methylation were observed, similar to those seen in the CDAHFD-fed MASH model. This study reveals the transcriptomic and metabolomic features of the MASH model mice and proposes a novel link between hepatic fibrogenesis and epigenetic histone modification in the context of metabolic dysfunction–associated steatotic liver disease/ MASH. The incidence of metabolic dysfunction–associated steatotic liver disease (MASLD) is increasing worldwide (1). Advanced MASLD is called metabolic dysfunction–associated steatohepatitis (MASH), which is characterized by severe inflammation and exacerbation of fibrogenesis. MASH also progresses to chronic liver disease, cirrhosis, and liver cancer. * For correspondence: Takashi Hosono, [hosono.takashi@nihon-u.ac.jp](hosono.takashi@nihon-u.ac.jp). MASLD–MASH induction may be explicable by reference to the multiple parallel-hit hypothesis (2), where lipotoxicity, cytokine production, oxidative stress, and activation of cellular signaling pathways promote inflammation or viceversa. There are a few clinical strategies for the prevention or treatment of MASLD–MASH. Various experimental animal models—such as genetically modified models, chemical toxicant models, and diet-induced models—have been established to investigate MASLD–MASH pathology (3, 4). There is a well-established and reproducible methionine-restricted choline-deficient L-amino acid–defined high-fat diet (CDAHFD)–induced MASH mouse model (5, 6). The CDAHFD–MASH model shows steatosis, liver inflammation, and fibrosis in a shorter time than other models (6). Decreased phosphatidylcholine synthesis and subsequently impaired excretion of lipids from the liver may cause steatosisand fibrosis (5), similar to the methionine-a

FAQs

What mouse model was used to study hepatic fibrogenesis in MASH?

The study used a choline-deficient L-amino acid–defined high-fat diet (CDAHFD)-induced MASH model, and it also examined a Gubra–amylin diet-fed ob/ob mouse model.

Which metabolomic changes were associated with fibrogenesis in the CDAHFD model?

The liver showed increased pentose phosphate pathway activity, elevated S-adenosylmethionine (SAM), and an increased SAM/SAH ratio.

How did altering SAM metabolism affect fibrogenic signaling?

SAM synthesis inhibition by cycloleucine suppressed activation of fibrogenic signaling and subsequent fibrogenesis in the liver.

Sep 30, 2026

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