CYP2C29 Monooxygenase Promotes CDAA-HFD-Induced Liver Fibrosis

Cytochrome P450 (CYP) monooxygenases (predominately the CYP2C and CYP2J isoforms) catalyze the oxidative metabolism of polyunsaturated fatty acids to generate epoxy fatty acids (EpFAs) and fatty acid diols, which are bioactive lipid signaling molecules that regulate inflammation and other important biological processes. Animal and human studies suggest that this pathway is dysregulated in metabolic dysfunction-associated steatohepatitis (MASH) and related liver diseases; however, its functional role in disease development of MASH, especially liver fibrosis, remains poorly understood. Here, we investigated the role of CYP2C29, the predominant CYP2C/2J isoform in mouse livers, in a choline-deficient, L-amino acid–defined, high-fat diet (CDAA-HFD)-induced liver fibrosis model. Compared with wild-type (WT) mice, CYP2C29 knockout (KO) mice exhibited reduced hepatic concentrations of CYP-derived EpFAs and fatty acid diols and attenuated development of liver fibrosis. Transcriptomic analysis further revealed that Cyp2c29 disruption suppressed the hepatic expression of multiple pro-fibrogenic, pro-inflammatory, and pro-angiogenic genes. Together, these findings demonstrate that the CYP monooxygenase pathway promotes the development of CDAA-HFD-induced liver fibrosis and its associated disorders. Overall design: 7 WT and 7 CYP2C29 KO mice were fed the CDAA-HFD diet (Research Diets, catalog no. A06071302, New Brunswick, NJ; detailed formulation in Table S2) for 16 weeks. Liver RNA was extracted and analyzed by RNA Sequencing