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 (Pparafl/fl) and hepatocyte-specific Ppara-disrupted (PparaΔHep) mice were fed a diet with or without a clinically relevant dose of PEM (0.00005%) for four weeks. In Pparafl/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 PparaΔHep 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.
Zhang et al. (2026) studied this question.