TY - JOUR
T1 - Discovery of peroxisome proliferator-activated receptor α (PPARα) activators with a ligand-screening system using a human PPARα-expressing cell line
AU - Tachibana, Keisuke
AU - Yuzuriha, Tomohiro
AU - Tabata, Ryotaro
AU - Fukuda, Syohei
AU - Maegawa, Takashi
AU - Takahashi, Rika
AU - Tanimoto, Keiichi
AU - Tsujino, Hirofumi
AU - Nunomura, Kazuto
AU - Lin, Bangzhong
AU - Matsuura, Yoshiharu
AU - Tanaka, Toshiya
AU - Hamakubo, Takao
AU - Sakai, Juro
AU - Kodama, Tatsuhiko
AU - Kobayashi, Tadayuki
AU - Ishimoto, Kenji
AU - Miyachi, Hiroyuki
AU - Doi, Takefumi
N1 - Funding Information:
This work was supported in part by JSPS KAKENHI Grants 15H02896, 16K13044, and 18H03190; Lydia O’Leary Memorial Pias Dermatological Foundation; Takeda Science Foundation; the Platform Project for Support-ing Drug Discovery and Life Science Research (Basis for Supporting Inno-vative Drug Discovery and Life Science Research (BINDS)) funded by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED) under Grants 17am0101084j0001, JP18am0101123, JP18am0101084, and JP18am0101085. The authors declare that they have no conflicts of inter-est with the contents of this article.
Publisher Copyright:
© 2018 Tachibana et al.
PY - 2018/6/29
Y1 - 2018/6/29
N2 - Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα 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 PPARα to quantify the effects of chemical ligands on PPARα activity. Using the established cell-based PPARα-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 PPARα agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPARα transcriptional activity, leading to PPARα 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 PPARα 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 PPARα to manage dyslipidemia.
AB - Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα 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 PPARα to quantify the effects of chemical ligands on PPARα activity. Using the established cell-based PPARα-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 PPARα agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPARα transcriptional activity, leading to PPARα 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 PPARα 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 PPARα to manage dyslipidemia.
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U2 - 10.1074/jbc.RA118.002077
DO - 10.1074/jbc.RA118.002077
M3 - Article
C2 - 29764933
AN - SCOPUS:85049609796
SN - 0021-9258
VL - 293
SP - 10333
EP - 10343
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -