Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice.
Farnesoid X receptor (FXR), the primary bile acid-sensing nuclear receptor, also plays a role in the stimulation of liver regeneration. Whole body deletion of FXR results in significant inhibition of liver regeneration after partial hepatectomy (PHX). FXR is expressed in the liver and intestines, and recent reports indicate that FXR regulates a distinct set of genes in a tissue-specific manner. These data raise a question about the relative contribution of hepatic and intestinal FXR in the regulation of liver regeneration. We studied liver regeneration after PHX in hepatocyte-specific FXR knockout (hepFXR-KO) mice over a time course of 0-14 days. Whereas the overall kinetics of liver regrowth in hepFXR-KO mice was unaffected, a delay in peak hepatocyte proliferation from day 2 to day 3 after PHX was observed in hepFXR-KO mice compared with Cre(-) control mice. Real-time polymerase chain reaction, western blot and co-immunoprecipitation studies revealed decreased cyclin D1 expression and decreased association of cyclin D1 with CDK4 in hepFXR-KO mice after PHX, correlating with decreased phosphorylation of the Rb protein and delayed cell proliferation in the hepFXR-KO livers. The hepFXR-KO mice also exhibited delay in acute hepatic fat accumulation following PHX, which is associated with regulation of cell cycle. Further, a significant delay in hepatocyte growth factor-initiated signaling, including the AKT, c-myc, and extracellular signal-regulated kinase 1/2 pathways, was observed in hepFXR-KO mice. Ultraperformance liquid chromatography/mass spectroscopy analysis of hepatic bile acids indicated no difference in levels of bile acids in hepFXR-KO and control mice.


CONCLUSIONS
Deletion of hepatic FXR did not completely inhibit but delays liver regeneration after PHX secondary to delayed cyclin D1 activation.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Prachi
P
Borude
Genea
G
Edwards
Chad
C
Walesky
Feng
F
Li
Xiaochao
X
Ma
Bo
B
Kong
Grace L
GL
Guo
Udayan
U
Apte
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D015870:Gene Expression; D016758:Genes, jun; D016259:Genes, myc; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D050152:Intra-Abdominal Fat; D008099:Liver / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D016160:Retinoblastoma Protein; D000099150:Receptor, Farnesoid X-Activated; C495902:Cdk4 protein, mouse