Antcins, triterpenoids from Antrodia cinnamomea, as new agonists for peroxisome proliferator-activated receptor α

Yu-Jen Wang ^a, Shih-Chin Lee ^a, Chun-Hua Hsu ^b, Yueh-Hsiung Kuo ^c,d,e, Chien-Chih Yang ^a, Fu-Jung Lin ^a,f,*

^a Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan

^b Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan

^c Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan

^d Department of Biotechnology, Asia University, Taichung, Taiwan

^e Chinese Medicine Research Center, China Medical University, Taichung, Taiwan

^f Research Center for Development Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan

Peroxisome proliferator-activated receptor a (PPARa) is a nuclear hormone receptor that transcriptionally regulates lipid metabolism and inflammation; therefore, PPARa agonists are promising agents to treat dyslipidemia and metabolic disorders. PPARa full agonists, such as fibrates, are effective anti-hypertriglyceride agents, but their use is limited by adverse side effects. Hence, the aim of this study was to identify small molecules that can activate PPARa while minimizing the adverse effects. Antrodia cinnamomea, a rare medical mushroom, has been used widely in Asian countries for the treatment of various diseases, including liver diseases. Antcin B, H and K (antcins) and ergostatrien-3b-ol (EK100) are bioactive compounds isolated from A. cinnamomea with anti-inflammatory actions. Antcins, ergostane-type triterpenoids, contain the polar head with carboxylate group and the sterol-based body. Here, we showed at the first time that sterol-based compounds, antcins, but not EK100, activate PPARa in a cell-based transactivation study. The in silico docking studies presented several significant molecular interactions of antcins, including Tyr314, and His440 in the ligand-binding domain of PPARa, and these interactions are required for helix 12 (H12) stabilization. We propose that PPARa activation activity of antcins is related to their binding mode which requires conventional H12 stabilization, and that antcins can be developed as safe selective PPARa modulators.

Keywords: Antrodia cinnamomea, Drug discovery, Metabolism, Nuclear receptor, Peroxisome proliferator-activated, receptor α