5Alpha-bile alcohols function as farnesoid X receptor antagonists.
The farnesoid X receptor (FXR) is a bile acid/alcohol-activated nuclear receptor that regulates lipid homeostasis. Unlike other steroid receptors, FXR binds bile acids in an orientation that allows the steroid nucleus A ring to face helix 12 in the receptor, a crucial domain for coactivator-recruitment. Because most naturally occurring bile acids and alcohols contain a cis-oriented A ring, which is distinct from that of other steroids and cholesterol metabolites, we investigated the role of this 5beta-configuration in FXR activation. The results showed that the 5beta-(A/B cis) bile alcohols 5beta-cyprinol and bufol are potent FXR agonists, whereas their 5alpha-(A/B trans) counterparts antagonize FXR transactivation and target gene expression. Both isomers bound to FXR, but their ability to induce coactivator-recruitment and thereby induce transactivation differed. These findings suggest a critical role for the A-ring orientation of bile salts in agonist/antagonist function.
Nishimaki-Mogami
Tomoko
T
National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan. mogami@nihs.go.jp
Kawahara
Yosuke
Y
Tamehiro
Norimasa
N
Yoshida
Takemi
T
Inoue
Kazuhide
K
Ohno
Yasuo
Y
Nagao
Taku
T
Une
Mizuho
M
D045744:Cell Line, Tumor; D002777:Cholestanols / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017930:Genes, Reporter; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
D002777:Cholestanols; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated