Nonalcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation in hepatocytes, causes liver fibrosis and cancer. Peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated transcription factor, is predominantly expressed in the liver, where it activates fatty acid catabolism and reduces plasma triglyceride levels. Recent studies suggest that PPARα is a good therapeutic target for NASH. In this study, to detect PPARα activators, we established reporter cell lines to quantify the effects of ligands on PPARα activity using a tightly tetracycline-regulated human hepatoblastoma cell line that can be induced to express full-length human PPARα. By screening a chemical library using this cell line, we successfully identified 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives as hit compounds with different basic skeletons from those of known PPARα agonists. This compound upregulated PPARα transcriptional activity in a dose-dependent manner, and induced PPARα target genes both in vitro and in vivo. Treatment of NASH model mice with this compound via oral gavage for 6 weeks led to a reduction in the plasma triglyceride level and a slight decrease in the liver hydroxyproline content. We are currently conducting X-ray crystallographic studies of the PPARα ligand-binding domain and complexes of these compounds to design and develop more effective drugs. Although further investigations are needed, this novel PPARα ligand might be a candidate drug for treating NASH.