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Journal of Lipid Research, Vol. 46, 458-468, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling

Andrew M. Anisfeld^*, Heidi R. Kast-Woelbern^*, Hans Lee^*, Yanqiao Zhang^*, Florence Y. Lee^* and Peter A. Edwards^1,*,

^* Department of Biological Chemistry and Medicine, University of California Los Angeles, Los Angeles, CA 90095
Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095

¹ To whom correspondence should be addressed. e-mail: pedwards{at}mednet.ucla.edu

Three genes, fibrinogen- (FBG), -ß, and -, 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 FBGß 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 FBGß 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.

Abbreviations: apoC-II, apolipoprotein C-II; CDCA, chenodeoxycholic acid; DR-1, direct repeat with a 1 bp spacer; ER-8, everted repeat with an 8 bp spacer; FBG, fibrinogen; FXR, farnesoid X receptor; FXRE, farnesoid X receptor response element; GW4064, 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole; hFXR, human farnesoid X receptor; hRXR, human retinoid X receptor ; I-BABP, ileal bile acid binding protein; IL-6, interleukin-6; IR-1, inverted repeat with a 1 bp spacer; LG100153, a synthetic RXR agonist; mFXR, murine farnesoid X receptor; MRP2, multidrug resistance-associated protein 2; PLTP, phospholipid transfer protein; PXR, pregnane X receptor; rFXR, rat farnesoid X receptor; RXR, retinoid X receptor ; SDC1, syndecan-1; SHP, small heterodimer partner

Supplementary key words farnesoid X receptor • chenodeoxycholic acid • 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole • nuclear hormone receptor

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