Regulation of carbohydrate metabolism by the farnesoid X receptor.
The farnesoid X receptor (FXR; NR1H4) is a nuclear hormone receptor that functions as the bile acid receptor. In addition to the critical role FXR plays in bile acid metabolism and transport, it regulates a variety of genes important in lipoprotein metabolism. We demonstrate that FXR also plays a role in carbohydrate metabolism via regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression. Treatment of either H4IIE or MH1C1 rat hepatoma cell lines as well as primary rat or human hepatocytes with FXR agonists led to stimulation of PEPCK mRNA expression to levels comparable to those obtained with glucocorticoid receptor agonists. We examined the physiological significance of FXR agonist-induced enhancement of PEPCK expression in primary rat hepatocytes. In addition to inducing PEPCK expression in primary hepatocytes, FXR agonists stimulated glucose output to levels comparable to those observed with a glucocorticoid receptor agonist. Consistent with these observations, treatment of C57BL6 mice with GW4064 significantly increased hepatic PEPCK expression. Activation of FXR initiated a cascade involving induction of peroxisome proliferator-activated receptor alpha and TRB3 expression that is consistent with stimulation of PEPCK gene expression via interference with a pathway that may involve Akt-dependent phosphorylation of Forkhead/winged helix transcription factor (FOXO1). The FXR-peroxisome proliferator-activated receptor alpha-TRB3 pathway was conserved in rat hepatoma cell lines, mice, as well as primary human hepatocytes. Thus, in addition to its role in the regulation of lipid metabolism, FXR regulates carbohydrate metabolism.
Stayrook
Keith R
KR
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Bramlett
Kelli S
KS
Savkur
Rajesh S
RS
Ficorilli
James
J
Cook
Todd
T
Christe
Michael E
ME
Michael
Laura F
LF
Burris
Thomas P
TP
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007555:Isoxazoles / Q000494:pharmacology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D047493:PPAR alpha / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000502:physiology; D010766:Phosphorylation; D011282:Pregnenediones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002241:Carbohydrates; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D005947:Glucose; D007555:Isoxazoles; D008074:Lipoproteins; D047493:PPAR alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D011282:Pregnenediones; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C023617:pregna-4,17-diene-3,16-dione; C412815:GW 4064