PRDX2 deficiency increases MCD-induced nonalcoholic steatohepatitis in female mice

Objective: To evaluate the role of PRDX2 in nonalcoholic steatohepatitis (NASH). Methods: NASH was induced in wild-type (WT) mice and liver-specific PRDX2 knockout (PRDX2 LKO) mice that were fed a methionine-choline deficient diet (MCD) for 5 weeks. Assessments of PRDX2 LKO's impact on the pathogenesis of NASH include histological analyses, quantitative PCR (q-PCR), western blotting (WB), and RNA sequencing (RNA-Seq). Results: PRDX2 LKO mice exhibited a significant increase in hepatic lipid accumulation and inflammation compared to WT mice after MCD feeding. PRDX2 KO markedly elevated circulating levels of aspartate aminotransferase (AST) and the pro-inflammatory signaling pathways within the liver. There was a notable increase in the activities of signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kappa B). We also found that PRDX2 KO significantly increased the extent of lipid peroxidation in the liver, most likely owing to the impaired peroxidase activity of PRDX2. Of interest, these findings were observed only in MCD-fed female mice, suggesting the sexual dimorphism of PRDX2 KO in MCD-induced NASH. Conclusion: PRDX2 deficiency increases MCD-induced NASH in female mice, suggesting a protective role for PRDX2.