We previously demonstrated that a clinically relevant dose of pemafibrate (PEM), a selective peroxisome proliferator-activated receptor α (PPARα) modulator (SPPARMα), reduces serum triglyceride (TG) levels in mice via hepatic PPARα activation. However, the specific contribution of hepatocyte PPARα remains unclear. To address this, male Ppara-floxed (Ppara^fl/fl) and hepatocyte-specific Ppara-disrupted (Ppara^ΔHep) mice were fed a diet with or without a clinically relevant dose of PEM (0.00005%) for four weeks. In Ppara^fl/fl mice, PEM significantly reduced circulating TG and non-esterified fatty acid levels by enhancing hepatic fatty acid uptake and β-oxidation. In contrast, these effects were absent in Ppara^ΔHep mice. Notably, PEM did not activate PPARα in extrahepatic tissues, including white/brown adipose tissue, kidney, and skeletal muscle in either genotype. These findings underscore the essential role of hepatocyte PPARα in mediating the pharmacological effects of PEM at clinically relevant doses.

Pemafibrate (PEM), a novel selective peroxisome proliferator-activated receptor α modulator, is widely used to treat dyslipidemia, yet its systemic metabolic effects remain incompletely defined. We performed untargeted serum metabolomics in patients with hypertriglyceridemia at baseline and at 2 and 8 weeks after PEM treatment. PEM increased cystine, L-methionine, uridine, and L-carnitine, while decreasing lipid-related metabolites, including lysophosphatidylcholines, adenosine, and erucic acid (22:1). Circulating carnitine levels rose progressively, with a significant elevation at 8 weeks, whereas ketone bodies showed only modest, non-significant increases. Consistently, increases in circulating and tissue carnitine were also observed in male 8-week-old C57BL/6J mice treated with a clinically relevant dose of PEM for 2 weeks. Mechanistically, PEM did not significantly alter genes involved in carnitine biosynthesis or transport, but upregulated hepatic carnitine O-acetyltransferase and carnitine O-octanoyltransferase, key enzymes of carnitine utilization and turnover. Collectively, these findings suggest that enhanced carnitine metabolism represents an important metabolic axis of PEM action.