Farnesoid X receptor protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo.
The farnesoid X receptor (FXR) is a key metabolic regulator in the liver by maintaining the homeostasis of liver metabolites. Recent findings suggest that FXR may have a much broader function in liver physiology and pathology. In the present work, we identify a novel role of FXR in protecting liver cell from apoptosis induced by nutritional withdrawal including serum deprivation in vitro or starvation in vivo. Two FXR ligands, chenodeoxycholic acid (CDCA) and GW4064, rescued HepG2 cells from serum deprivation-induced apoptosis in a dose-dependent manner. This effect of FXR on apoptotic suppression was compromised when FXR was knocked down by short interfering RNA. Similarly, the effects of both CDCA and GW4064 were abolished after inhibition of the MAPK pathway by a specific inhibitor of MAPK kinase 1/2. Immunoblotting results indicated that FXR activation by CDCA and GW4064 induced ERK1/2 phosphorylation, which was attenuated by serum deprivation. In vivo, FXR(-/-) mice exhibited an exacerbated liver apoptosis and lower levels of phosphorylated-ERK1/2 compared to wild-type mice after starvation. In conclusion, our results suggest a novel role of FXR in modulating liver cell apoptosis.
Wang
Yan-Dong
YD
Department of Gene Regulation and Drug Discovery, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA 91010, USA.
Yang
Fan
F
Chen
Wei-Dong
WD
Huang
Xiongfei
X
Lai
Lily
L
Forman
Barry M
BM
Huang
Wendong
W
D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064