Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition.
The farnesoid X receptor (FXR) is a key sensor in bile acid homeostasis. Although four human FXR isoforms have been identified, the physiological role of this diversity is poorly understood. Here we investigated their subcellular localization, agonist sensitivity and response of target genes. Measurement of mRNA revealed that liver predominantly expressed FXRα1(+/-), whereas FXRα2(+/-) were the most abundant isoforms in kidney and intestine. In all cases, the proportion of FXRα(1/2)(+) and FXRα(1/2)(-) isoforms, i.e., with and without a 12bp insert, respectively, was approximately 50%. When FXR was expressed in liver and intestinal cells the magnitude of the response to GW4064 and bile acids differs among FXR isoforms. In both cell types the strongest response was that of FXRα1(-). Different efficacy of bile acids species to activate FXR was found. The four FXR isoforms shared the order of sensitivity to bile acids species. When in FXR-deficient cells FXR was transfected, unconjugated, but not taurine- and glycine-amidated bile acids, were able to activate FXR. In contrast, human hepatocytes and cell lines showing an endogenous expression of FXR were sensitive to both unconjugated and conjugated bile acids. This suggests that to activate FXR conjugated, but not unconjugated, bile acids require additional component(s) of the intracellular machinery not related with uptake processes, which are missing in some tumor cells. In conclusion, cell-specific pattern of FXR isoforms determine the overall tissue sensitivity to FXR agonists and may be involved in the differential response of FXR target genes to FXR activation.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
Javier
J
Vaquero
Maria J
MJ
Monte
Mercedes
M
Dominguez
Jordi
J
Muntané
Jose J G
JJ
Marin
D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D005998:Glycine / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013654:Taurine / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D005998:Glycine; D007555:Isoxazoles; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D013654:Taurine; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064
ACA; BA; BSEP; CA; CDCA; DCA; FGF; FXR; GCDCA; Glycoconjugated bile acids; IBABP; Ileum; LCA; Liver; Nuclear receptor; OATP; OST; RXR; SHP; TCDCA; Tauroconjugated bile acids; UDCA; allocholic acid; bile acid; bile salt export pump; chenodeoxycholic acid; cholic acid; deoxycholic acid; farnesoid X receptor; fibroblast growth factor; glycochenodeoxycholic acid; ileal bile acid binding protein; lithocholic acid; organic anion transporter polipeptide; organic solute transporter; retinoid X receptor; small heterodimer partner; taurochenodeoxycholic acid; ursodeoxycholic acid