Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor alpha (PPAR alpha) modulator whose binding efficiency to PPAR alpha is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPAR alpha stimulation and the enhancement of fatty acid uptake and beta-oxidation. Interestingly, PPAR alpha was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPAR alpha. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting.

Automated summary

Pemafibrate (PEM) is a novel lipid-lowering drug that can efficiently reduce serum triglyceride (TG) levels and increase fibroblast growth factor 21 (FGF21) without causing hepatotoxicity in mice when used at a clinically relevant dose. It binds to peroxisome proliferator-activated receptor alpha (PPAR alpha) and activates it specifically in the liver, leading to enhanced fatty acid uptake and beta-oxidation.