| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Lilly Research Laboratories, Lilly Corporate Center (K.R.S., K.S.B., R.S.S., J.F., T.C., M.E.C., L.F.M., T.P.B.), Indianapolis, Indiana 46285; and Department of Pharmacology and Toxicology, Indiana University School of Medicine (K.S.B., T.P.B.), Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Dr. Thomas P. Burris, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285. E-mail: burris{at}lilly.com.
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 
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 -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.
This article has been cited by other articles:
 |
|
 |
|
  K. R. Stayrook, P. M. Rogers, R. S. Savkur, Y. Wang, C. Su, G. Varga, X. Bu, T. Wei, S. Nagpal, X. S. Liu, et al. Regulation of Human 3{alpha}-Hydroxysteroid Dehydrogenase (AKR1C4) Expression by the Liver X Receptor {alpha} Mol. Pharmacol., February 1, 2008; 73(2): 607 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Jiang, X. X. Wang, P. Scherzer, P. Wilson, J. Tallman, H. Takahashi, J. Li, M. Iwahashi, E. Sutherland, L. Arend, et al. Farnesoid X Receptor Modulates Renal Lipid Metabolism, Fibrosis, and Diabetic Nephropathy Diabetes, October 1, 2007; 56(10): 2485 - 2493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Marzolini, R. G. Tirona, G. Gervasini, B. Poonkuzhali, M. Assem, W. Lee, B. F. Leake, J. D. Schuetz, E. G. Schuetz, and R. B. Kim A Common Polymorphism in the Bile Acid Receptor Farnesoid X Receptor Is Associated with Decreased Hepatic Target Gene Expression Mol. Endocrinol., August 1, 2007; 21(8): 1769 - 1780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hu, M. Chouinard, A. L. Cox, P. Sipes, M. Marcelo, J. Ficorilli, S. Li, H. Gao, T. P. Ryan, M. D. Michael, et al. Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation J. Biol. Chem., December 29, 2006; 281(52): 39831 - 39838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Swales, M. Korbonits, R. Carpenter, D. T. Walsh, T. D. Warner, and D. Bishop-Bailey The farnesoid x receptor is expressed in breast cancer and regulates apoptosis and aromatase expression. Cancer Res., October 15, 2006; 66(20): 10120 - 10126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, X. Kong, E. Owsley, E. Ellis, S. Strom, and J. Y. L. Chiang Insulin Regulation of Cholesterol 7{alpha}-Hydroxylase Expression in Human Hepatocytes: ROLES OF FORKHEAD BOX O1 AND STEROL REGULATORY ELEMENT-BINDING PROTEIN 1c J. Biol. Chem., September 29, 2006; 281(39): 28745 - 28754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Cariou, K. van Harmelen, D. Duran-Sandoval, T. H. van Dijk, A. Grefhorst, M. Abdelkarim, S. Caron, G. Torpier, J.-C. Fruchart, F. J Gonzalez, et al. The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice J. Biol. Chem., April 21, 2006; 281(16): 11039 - 11049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, F. Y. Lee, G. Barrera, H. Lee, C. Vales, F. J. Gonzalez, T. M. Willson, and P. A. Edwards Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice PNAS, January 24, 2006; 103(4): 1006 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Hanniman, G. Lambert, T. C. McCarthy, and C. J. Sinal Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice J. Lipid Res., December 1, 2005; 46(12): 2595 - 2604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Duran-Sandoval, B. Cariou, F. Percevault, N. Hennuyer, A. Grefhorst, T. H. van Dijk, F. J. Gonzalez, J.-C. Fruchart, F. Kuipers, and B. Staels The Farnesoid X Receptor Modulates Hepatic Carbohydrate Metabolism during the Fasting-Refeeding Transition J. Biol. Chem., August 19, 2005; 280(33): 29971 - 29979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Cariou, D. Duran-Sandoval, F. Kuipers, and B. Staels Farnesoid X Receptor: A New Player in Glucose Metabolism? Endocrinology, March 1, 2005; 146(3): 981 - 983. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
