Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts.
The nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock-out mice (FXR(-/-)) by CCl(4) intoxication, 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.)-infection. In addition, we determined nuclear receptor expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse hepatic stellate cells (HSCs), portal myofibroblasts (MFBs), and human HSCs. Cell type-specific FXR protein expression was determined by immunohistochemistry in five mouse models and prototypic human fibrotic liver diseases. Expression of nuclear receptors was much lower in mouse and human HSCs/MFBs compared with total liver expression with the exception of vitamin D receptor. FXR protein was undetectable in mouse and human HSCs and MFBs. FXR loss had no effect in CCl(4)-intoxicated and S.m.-infected mice, but significantly decreased liver fibrosis of the biliary type (common bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocollidine). These data suggest that FXR loss significantly reduces fibrosis of the biliary type, but has no impact on non-cholestatic liver fibrosis. Since there is no FXR expression in HSCs and MFBs in liver fibrosis, our data indicate that these cells may not represent direct therapeutic targets for FXR ligands.
Fickert
Peter
P
Laboratory of Experimental and Molecular Hepatology, Medical University Graz, Graz, Austria.
Fuchsbichler
Andrea
A
Moustafa
Tarek
T
Wagner
Martin
M
Zollner
Gernot
G
Halilbasic
Emina
E
Stöger
Ulrike
U
Arrese
Marco
M
Pizarro
Margarita
M
Solís
Nancy
N
Carrasco
Gonzalo
G
Caligiuri
Alessandra
A
Sombetzki
Martina
M
Reisinger
Emil
E
Tsybrovskyy
Oleksiy
O
Zatloukal
Kurt
K
Denk
Helmut
H
Jaeschke
Hartmut
H
Pinzani
Massimo
M
Trauner
Michael
M
D000818:Animals; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006500:Hepatic Duct, Common / Q000166:cytology; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099150:Receptor, Farnesoid X-Activated
D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated