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

Abstract

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 well-established 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 CDAHFD-fed 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.