1-phenyl-3-methyl-5-pyrazolone activates the AMPK pathway to alleviate western-diet induced metabolic dysfunction-associated steatohepatitis in mice

Abstract

Background & aims: Approved drugs for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) are limited, although it has become the most common chronic liver disease worldwide. 1-phenyl-3-methyl-5-pyrazolone (PMP) possesses various biological effects such as anti-inflammatory and antioxidant. However, the effects and underlying mechanism of PMP in MASH remain unclear.

Methods: Steatosis cells were induced by palmitate/oleic acid (PO). Then, the contents of lipids and reactive oxygen species were measured. To further investigate the effects of PMP on MASH models, C57BL/6J mice were fed a western diet (WD) for 24 weeks and PMP was administered daily by intragastric gavage. Serum enzymes and lipids were assayed by a biochemistry analyzer. RNA sequencing, real-time qPCR, and western blotting were used to measure the expression of different genes. Histological analysis of the liver included HE, Oil red O, and Sirius red staining.

Results: PMP alleviated lipid accumulation and oxidative stress induced by PO (P < 0.001). In vivo, WD-induced significant elevation of blood glucose and serum lipids were reduced by PMP (P < 0.05). Furthermore, PMP effectively prevented hepatic steatosis, inflammation, and fibrosis in MASH mice. Western blot results suggested PMP promoted the phosphorylation of LKB1 and AMPKα at T172, which is a marker of activation of the AMPK pathway. RNA sequencing also demonstrated that PMP facilitated the activation of the AMPK pathway. Furthermore, the protective effects of PMP on steatosis cells and MASH mice disappeared after treatment with an AMPK inhibitor.

Conclusions: PMP protects against metabolic-stress-induced MASH through activating AMPK signaling, indicating that PMP may be a candidate for MASH therapy in the future.

Keywords: 1-Phenyl-3-methyl-5-pyrazolone; AMP-Activated protein kinase; Edaravone; Metabolic dysfunction-associated steatohepatitis.