Peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator in hepatic lipid metabolism and a potential therapeutic target for dyslipidemia. However, in humans hepatic PPARalpha-regulated genes remain unclear. To investigate the effect of PPARalpha agonism on mRNA expressions of lipid metabolism-related genes in human livers, a potent PPARalpha agonist, KRP-101 (KRP), was used to treat the human hepatoma cell line, HepaRG cells. KRP did not affect AOX or L-PBE, which are involved in peroxisomal beta-oxidation. KRP increased L-FABP, CPT1A, VLCAD, and PDK4, which are involved in lipid transport or oxidation. However, the EC(50) values (114-2500 nM) were >10-fold weaker than the EC(50) value (10.9 nM) for human PPARalpha in a transactivation assay. To search for more sensitive genes, we determined the mRNA levels of apolipoproteins, apoA-I, apoA-II, apoA-IV, apoA-V, and apoC-III. KRP had no or little effect on apoA-I, apoC-III, and apoA-II. Interestingly, KRP increased apoA-IV (EC(50), 0.99 nM) and apoA-V (EC(50), 0.29 nM) with high sensitivity. We identified apoA-IV as a PPARalpha-upregulated gene in a study using PPARalpha siRNA. Moreover, when administered orally to dogs, KRP decreased the serum triglyceride level and increased the serum apoA-IV level in a dose-dependent manner. These findings suggest that apoA-IV, newly identified as a highly sensitive PPARalpha-regulated gene in human livers, may be one of the mechanisms underlying PPARalpha agonist-induced triglyceride decrease and HDL elevation.