5beta-Cholane activators of the farnesol X receptor.
The farnesoid X receptor (FXR) is activated by bile acids, natural agonists for this nuclear receptor. FXR-target genes play important roles in cholesterol and lipid metabolism. We have found that a series of 5beta-cholanic acid derivatives, even though without a hydroxyl group or any other substituent on the steroidal rings, can activate FXR more potently than hydroxylated bile acids in a reporter gene assay. The most potent compound among these derivatives, N-methyl-5beta-glycocholanic acid (NMGCA), induces the formation of receptor/coactivator complex in a gel-shift assay and also increases the expression of FXR target genes in human hepatoma HepG2 cells. Furthermore, in rats, NMGCA causes hypolipidemic effects as well as induction of the FXR target genes in liver. Our results suggest that NMGCA and its derivatives are important FXR activators in the study of the physiological functions of FXR and are potentially useful as pharmaceutical agents for treatment of cholesterol and lipid-related diseases.
Fukuchi
Junichi
J
Ben May Institute for Cancer Research, Department of Biochemistry and Molecular Biology, The University of Chicago, IL 60637, USA.
Song
Ching
C
Dai
Qing
Q
Hiipakka
Richard A
RA
Liao
Shutsung
S
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D002793:Cholic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D022762:CCAAT-Enhancer-Binding Proteins; D002784:Cholesterol; D002793:Cholic Acids; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C502003:N-methyl-5beta glycocholanic acid; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; C007036:cholanic acid