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Submitted on July 26, 2004
Accepted on November 19, 2004
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202
* To whom correspondence should be addressed. 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 that obtained with glucocorticoid receptor (GR) 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 the primary hepatocytes, FXR agonists stimulated glucose output to levels comparable to those observed with a GR 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 PPAR
and TRB3 expression that is consistent with stimulation of PEPCK gene expression via interference with a pathway that may involve Akt-dependent phosphorylation of FOXO1. The FXR - PPAR - TRB3 pathway was conserved in rat hepatoma cell lines, mice, as well as in primary human heptocytes. Thus, in addition to its role in regulation of lipid metabolism FXR also regulates carbohydrate metabolism.
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