Pin1 mediates metabolic dysfunction-associated steatohepatitis in mice fed high-fat, high-cholesterol diet by regulating both PPARα and acetyl CoA carboxylase

Metabolic dysfunction-associated steatohepatitis (MASH) has received increasing attention because of the increase in the number of affected patients. However, the mechanism underlying its onset is complicated and has not been completely elucidated. We recently reported increased Pin1 expression in the liver of patients with MASH. Therefore, we aimed to investigate the role of hepatocyte Pin1 in MASH development. Hepatocyte-specific Pin1-knockout (H-Pin1 KO) and Pin1-flox (WT) littermates were fed a high-fat, high-cholesterol diet for 16 weeks. The WT mice showed remarkable obesity, steatosis, liver fibrosis, and liver injury. Conversely, the H-Pin1 KO mice exhibited mild symptoms. One explanation of these phenomena was that Pin1 interacted with acetyl CoA carboxylase (ACC) and increased its expressions in the liver without affecting its phosphorylation. In addition, RNA sequencing analysis revealed that Pin1 deficiency in hepatocytes promoted the pathway of fatty acid degradation, including peroxisome proliferator-activated receptor alpha (PPARα) signaling in the livers. Indeed, we found that Pin1 silencing upregulated the expressions of PPARα-target genes in vitro and in vivo. Consistent with these results, Pin1 deficiency in hepatocytes elevated serum fibroblast growth factor 21 (FGF21) concentrations, which is a representative target of PPARα, and serum beta-hydroxybutyrate produced by fatty acid oxidation. Importantly, we also reveal that Pin1 binds with PPARα, downregulating its transcription without affecting its expression levels or translocation. Taken together, our findings indicate that Pin1 acts as a critical mediator of MASH development by regulating both PPARα and ACC1. Hence, developing selective Pin1 inhibitors may be beneficial for treating MASH.