Highly sensitive upregulation of apolipoprotein A-IV by peroxisome proliferator-activated receptor α (PPARα) agonist in human hepatoma cells

Peroxisome proliferator-activated receptor α (PPARα) is a key regulator in hepatic lipid metabolism and a potential therapeutic target for dyslipidemia. However, in humans hepatic PPARα-regulated genes remain unclear. To investigate the effect of PPARα agonism on mRNA expressions of lipid metabolism-related genes in human livers, a potent PPARα 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 β-oxidation. KRP increased L-FABP, CPT1A, VLCAD, and PDK4, which are involved in lipid transport or oxidation. However, the EC50 values (114–2500 nM) were >10-fold weaker than the EC50 value (10.9 nM) for human PPARα 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 (EC50, 0.99 nM) and apoA-V (EC50, 0.29 nM) with high sensitivity. We identified apoA-IV as a PPARα-upregulated gene in a study using PPARα 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 PPARα-regulated gene in human livers, may be one of the mechanisms underlying PPARα agonist-induced triglyceride decrease and HDL elevation.