The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition.
The liver plays a central role in the control of blood glucose homeostasis by maintaining a balance between glucose production and utilization. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor. Hepatic FXR expression is regulated by glucose and insulin. Here we identify a role for FXR in the control of hepatic carbohydrate metabolism. When submitted to a controlled fasting-refeeding schedule, FXR(-/-) mice displayed an accelerated response to high carbohydrate refeeding with an accelerated induction of glycolytic and lipogenic genes and a more pronounced repression of gluconeogenic genes. Plasma insulin and glucose levels were lower in FXR(-/-) mice upon refeeding the high-carbohydrate diet. These alterations were paralleled by decreased hepatic glycogen content. Hepatic insulin sensitivity was unchanged in FXR(-/-) mice. Treatment of isolated primary hepatocytes with a synthetic FXR agonist attenuated glucose-induced mRNA expression as well as promoter activity of L-type pyruvate kinase, acetyl-CoA carboxylase 1, and Spot14. Moreover, activated FXR interfered negatively with the carbohydrate response elements regions. These results identify a novel role for FXR as a modulator of hepatic carbohydrate metabolism.
Duran-Sandoval
Daniel
D
U.R. 545 INSERM, Atherosclerosis Department, Pasteur Institute of Lille and the Faculty of Pharmacy, Lille2 University, France.
Cariou
Bertrand
B
Percevault
Fredéric
F
Hennuyer
Nathalie
N
Grefhorst
Aldo
A
van Dijk
Theo H
TH
Gonzalez
Frank J
FJ
Fruchart
Jean-Charles
JC
Kuipers
Folkert
F
Staels
Bart
B
D000818:Animals; D050260:Carbohydrate Metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005215:Fasting / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D005943:Gluconeogenesis; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated