Discovery of peroxisome proliferator-activated receptor (PPAR alpha) activators with a ligand-screening system using a human PPAR-expressing cell line

作者：Tachibana Keisuke^*; Yuzuriha Tomohiro; Tabata Ryotaro; Fukuda Syohei; Maegawa Takashi; Takahashi Rika; Tanimoto Keiichi; Tsujino Hirofumi; Nunomura Kazuto; Lin Bangzhong; Matsuura Yoshiharu; Tanaka Toshiya; Hamakubo Takao; Sakai Juro; Kodama Tatsuhiko; Kobayashi Tadayuki; Ishimoto Kenji; Miyachi Hiroyuki; Doi Takefumi^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293(26): 10333-10343.

DOI：10.1074/jbc.RA118.002077

• peroxisome proliferator-activated receptor (PPAR)
• triglyceride
• cell biology
• transcription regulation
• drug screening
• chemical screening system
• dyslipidemia
• ligand
• nuclear receptor
• Tet-off system

Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPAR is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPAR activators are often used to treat patients with dyslipidemia. To discover additional PPAR activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator-responsive elements (PPREs) and tetracycline-regulated expression of full-length human PPAR to quantify the effects of chemical ligands on PPAR activity. Using the established cell-based PPAR-activator screening system to screen a library of >12,000 chemical compounds, we identified several hit compounds with basic chemical skeletons different from those of known PPAR agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPAR transcriptional activity, leading to PPAR target gene expression both in vitro and in vivo. Of note, the half-maximal effective concentrations of the hit compounds were lower than that of the known PPAR ligand fenofibrate. Finally, fenofibrate or compound 3 treatment of high fructose-fed rats having elevated plasma triglyceride levels for 14 days indicated that compound 3 reduces plasma triglyceride levels with similar efficiency as fenofibrate. These observations raise the possibility that 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives might be effective drug candidates for selective targeting of PPAR to manage dyslipidemia.

• 出版日期2018-6-29