Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis

Abstract

The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.

Inhibition of JNK signalling mediates PPARα‐dependent protection against intrahepatic cholestasis by fenofibrate

“…According to the transition method based on body surface area, the equivalent dose in mice is 22.5–45 mg·kg −1 . In a mouse nonalcoholic steatohepatitis model, fenofibrate at 50 mg·kg −1 ·day −1 improved obesity, dyslipidaemia, liver dysfunction and NASH pathology (Honda et al , ). In rodent models, fenofibrate at 100 and 200 mg·kg −1 ·day −1 partially improved ALP, γ‐glutamyl transferase, TBA, ALT, AST, TNF‐α and IL‐1β levels (Cindoruk et al , ; El‐Sisi et al , ).…”

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

“…After one-year treatment, clofibrate did not show any histological improvements in steatosis, inflammation, or fibrosis, nor a reduction in ALT, AST, GGT, bilirubin, or cholesterol, which led to the discontinuation of its evaluation [41]. Pemafibrate, a novel selective PPAR-α agonist, showed to ameliorate liver dysfunction in type 2 diabetes patients, and it was later demonstrated to also improve the NASH pathology in rodents by the stimulation of lipid metabolism and reducing inflammation [42,43].…”

Gene Expression Analysis of the Activating Factor 3/Nuclear Protein 1 Axis in a Non-alcoholic Steatohepatitis Mouse Model

“…35 It is also considered a therapeutic target. 36 Therefore, the suppression of PPAR-α by ER stress diminishes its protective effect and may promote NASH. On the other hand, ER stress induces cleavage of SREBP-1c and insulin resistance.…”