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Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4 , which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1 , FGF21 , and VLDLR . Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate