title: Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor.
abstract: TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. In the present study, we evaluated the ability of bile alcohols, which are structurally and physiologically similar to bile acids and are produced as the end products of cholesterol catabolism in evolutionarily primitive vertebrates, to act as TGR5 agonists. In a cell-based reporter assay and a cAMP production assay performed in vitro, most bile alcohols with a side chain containing hydroxyl group(s) were highly efficacious agonists for TGR5 comparable to its most potent ligand in the naturally occurring bile acid, lithocholic acid. However, the abilities of the bile alcohols to activate TGR5 varied with the position and number of the hydroxyl substituent in the side chain. Additionally, the conformation of the steroidal nucleus of bile alcohols is also important for its activity as a TGR5 agonist. Thus, we have provided new insights into the structure-activity relationships of bile alcohols as TGR5 agonists.
authors.affiliation: Laboratory of Organic and Bio-molecular Chemistry, Faculty of Pharmaceutical Science, Hiroshima International University, Kure, Japan. y-iguchi@ps.hirokoku-u.ac.jp
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Iguchi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Kenji
authors.initials: K
authors.lastname: Kihira
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Mizuho
authors.initials: M
authors.lastname: Une
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002777:Cholestanols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D008024:Ligands; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D002777:Cholestanols; C473772:GPBAR1 protein, human; D006878:Hydroxides; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; C031356:hydroxide ion