Serum Metabolomics Reveals Carnitine Metabolism as a Possible Central Metabolic Axis of Pemafibrate Action

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.