Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling.
Three genes, fibrinogen-alpha (FBGalpha), -beta, and -gamma, encode proteins that make up the mature FBG protein complex. This complex is secreted from the liver and plays a key role in coagulation in response to vascular disruption. We identified all three FBG genes in a screen designed to isolate genes that are regulated by the farnesoid X receptor (FXR; NR1H4). Treatment of human hepatoma cells with either naturally occurring or synthetic [3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole] FXR ligands resulted in the induction of transcripts for all three genes. The induction of FBGbeta mRNA in response to activated FXR appears to be a primary transcriptional response, as it is blocked by actinomycin D but not by cycloheximide. Four FXR isoforms were recently identified that differ either at their N termini and/or by the presence of four amino acids in the hinge region. Interestingly, the activities of the human FBGbeta promoter-reporter constructs were highly induced by FXR isoforms that lack the four amino acid insert. The observation that all three FBG subunits are induced by specific FXR isoforms, in response to FXR ligands, suggests that bile acids and FXR modulate fibrinolytic activity.
Anisfeld
Andrew M
AM
Department of Biological Chemistry and Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Kast-Woelbern
Heidi R
HR
Lee
Hans
H
Zhang
Yanqiao
Y
Lee
Florence Y
FY
Edwards
Peter A
PA
D001647:Bile Acids and Salts / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D005340:Fibrinogen / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D003513:Cycloheximide; D004268:DNA-Binding Proteins; D003609:Dactinomycin; D005340:Fibrinogen; D007555:Isoxazoles; D008024:Ligands; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated