Potential conflict of interest: Nothing to report.
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, pages 2344–2352, December 2012
How to Cite
Borude, P., Edwards, G., Walesky, C., Li, F., Ma, X., Kong, B., Guo, G. L. and Apte, U. (2012), Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology, 56: 2344–2352. doi: 10.1002/hep.25918
Supported by National Institutes of Health grant P20 RR021940 (U. A. and G. L. G.), AASLD/ALF Liver Scholar Award (U. A.), and National Institutes of Health grant R01 DK031343 and a University of Kansas endowment (G. L. G.).
- Issue published online: 4 DEC 2012
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 22 JUN 2012 08:46AM EST
- Manuscript Accepted: 10 JUN 2012
- Manuscript Received: 17 FEB 2012
- National Institutes of Health. Grant Number: P20 RR021940
- National Institutes of Health. Grant Number: R01 DK031343
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. Conclusion: Deletion of hepatic FXR did not completely inhibit but delays liver regeneration after PHX secondary to delayed cyclin D1 activation. (HEPATOLOGY 2012;56:2344–2352)