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

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear hormone receptor that transcriptionally regulates lipid metabolism and inflammation; therefore, PPAR alpha agonists are promising agents to treat dyslipidemia and metabolic disorders. PPAR alpha 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 PPAR alpha 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-3 beta-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 PPAR alpha 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 PPAR alpha, 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 PPAR alpha modulators. Copyright (C) 2018, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC.