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Departments of Biological Chemistry and Medicine (H.R.K., C.M.N., B.A.L., P.A.E.), University of California, Los Angeles, California 90095; Laboratory of Metabolism (C.J.S., F.J.G.,) Division of Basic Sciences, National Institutes of Health, Bethesda, Maryland 20892; Molecular Biology Institute (K.R., P.A.E.), University of California, Los Angeles, California 90095; GlaxoSmithKline (S.A.J., T.M.W.) Nuclear Receptor Discovery Research, Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Peter A. Edwards, Ph.D., Department of Biological Chemistry, University of California, Los Angeles, California 90095. E-mail: pedwards{at}mednet.ucla.edu
The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization to identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs demonstrate that recombinant FXR and RXR bind to two FXR response elements that are contained within two important distal enhancer elements (hepatic control regions) that lie 11 kb and 22 kb upstream of the transcription start site of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was activated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfer protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Finally, we observed decreased plasma triglyceride levels in mice fed cholic acid- containing diets. These results identify a mechanism whereby FXR and its ligands lower plasma triglyceride levels. These findings may have important implications in the clinical management of hyperlipidemias.
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E. Kim, S. Xie, S.-D. Yeh, Y.-F. Lee, L. L. Collins, Y.-C. Hu, C.-R. Shyr, X.-M. Mu, N.-C. Liu, Y.-T. Chen, et al. Disruption of TR4 Orphan Nuclear Receptor Reduces the Expression of Liver Apolipoprotein E/C-I/C-II Gene Cluster J. Biol. Chem., November 21, 2003; 278(47): 46919 - 46926. [Abstract] [Full Text] [PDF]
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G. L. Guo, G. Lambert, M. Negishi, J. M. Ward, H. B. Brewer Jr., S. A. Kliewer, F. J. Gonzalez, and C. J. Sinal Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity J. Biol. Chem., November 14, 2003; 278(46): 45062 - 45071. [Abstract] [Full Text] [PDF]
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T. Kok, C. V. Hulzebos, H. Wolters, R. Havinga, L. B. Agellon, F. Stellaard, B. Shan, M. Schwarz, and F. Kuipers Enterohepatic Circulation of Bile Salts in Farnesoid X Receptor-deficient Mice: EFFICIENT INTESTINAL BILE SALT ABSORPTION IN THE ABSENCE OF ILEAL BILE ACID-BINDING PROTEIN J. Biol. Chem., October 24, 2003; 278(43): 41930 - 41937. [Abstract] [Full Text] [PDF]
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B. G. Bhat, S. R. Rapp, J. A. Beaudry, N. Napawan, D. N. Butteiger, K. A. Hall, C. L. Null, Y. Luo, and B. T. Keller Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435 J. Lipid Res., September 1, 2003; 44(9): 1614 - 1621. [Abstract] [Full Text] [PDF]
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A. Zhao, J.-L. Lew, L. Huang, J. Yu, T. Zhang, Y. Hrywna, J. R. Thompson, N. de Pedro, R. A. Blevins, F. Pelaez, et al. Human Kininogen Gene Is Transactivated by the Farnesoid X Receptor J. Biol. Chem., August 1, 2003; 278(31): 28765 - 28770. [Abstract] [Full Text] [PDF]
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X. Prieur, H. Coste, and J. C. Rodriguez The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-{alpha} and Contains a Novel Farnesoid X-activated Receptor Response Element J. Biol. Chem., July 3, 2003; 278(28): 25468 - 25480. [Abstract] [Full Text] [PDF]
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A. Cachefo, P. Boucher, E. Dusserre, P. Bouletreau, M. Beylot, and C. Chambrier Stimulation of cholesterol synthesis and hepatic lipogenesis in patients with severe malabsorption J. Lipid Res., July 1, 2003; 44(7): 1349 - 1354. [Abstract] [Full Text] [PDF]
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A. M. Anisfeld, H. R. Kast-Woelbern, M. E. Meyer, S. A. Jones, Y. Zhang, K. J. Williams, T. Willson, and P. A. Edwards Syndecan-1 Expression Is Regulated in an Isoform-specific Manner by the Farnesoid-X Receptor J. Biol. Chem., May 23, 2003; 278(22): 20420 - 20428. [Abstract] [Full Text] [PDF]
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J. Cui, L. Huang, A. Zhao, J.-L. Lew, J. Yu, S. Sahoo, P. T. Meinke, I. Royo, F. Pelaez, and S. D. Wright Guggulsterone Is a Farnesoid X Receptor Antagonist in Coactivator Association Assays but Acts to Enhance Transcription of Bile Salt Export Pump J. Biol. Chem., March 14, 2003; 278(12): 10214 - 10220. [Abstract] [Full Text] [PDF]
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I. Pineda Torra, T. Claudel, C. Duval, V. Kosykh, J.-C. Fruchart, and B. Staels Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor {alpha} Gene via Activation of the Farnesoid X Receptor Mol. Endocrinol., February 1, 2003; 17(2): 259 - 272. [Abstract] [Full Text] [PDF]
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G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis J. Biol. Chem., January 17, 2003; 278(4): 2563 - 2570. [Abstract] [Full Text] [PDF]
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Y. Zhang, H. R. Kast-Woelbern, and P. A. Edwards Natural Structural Variants of the Nuclear Receptor Farnesoid X Receptor Affect Transcriptional Activation J. Biol. Chem., January 3, 2003; 278(1): 104 - 110. [Abstract] [Full Text] [PDF]
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P. A. Mak, H. R. Kast-Woelbern, A. M. Anisfeld, and P. A. Edwards Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors J. Lipid Res., December 1, 2002; 43(12): 2037 - 2041. [Abstract] [Full Text] [PDF]
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P. A. Mak, B. A. Laffitte, C. Desrumaux, S. B. Joseph, L. K. Curtiss, D. J. Mangelsdorf, P. Tontonoz, and P. A. Edwards Regulated Expression of the Apolipoprotein E/C-I/C-IV/C-II Gene Cluster in Murine and Human Macrophages. A CRITICAL ROLE FOR NUCLEAR LIVER X RECEPTORS alpha AND beta J. Biol. Chem., August 23, 2002; 277(35): 31900 - 31908. [Abstract] [Full Text] [PDF]
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J. Y. L. Chiang Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors Endocr. Rev., August 1, 2002; 23(4): 443 - 463. [Abstract] [Full Text] [PDF]
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J. Cui, T. S. Heard, J. Yu, J.-L. Lo, L. Huang, Y. Li, J. M. Schaeffer, and S. D. Wright The Amino Acid Residues Asparagine 354 and Isoleucine 372 of Human Farnesoid X Receptor Confer the Receptor with High Sensitivity to Chenodeoxycholate J. Biol. Chem., July 12, 2002; 277(29): 25963 - 25969. [Abstract] [Full Text] [PDF]
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P. A. Edwards, H. R. Kast, and A. M. Anisfeld BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis J. Lipid Res., January 1, 2002; 43(1): 2 - 12. [Abstract] [Full Text] [PDF]
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H. R. Kast, B. Goodwin, P. T. Tarr, S. A. Jones, A. M. Anisfeld, C. M. Stoltz, P. Tontonoz, S. Kliewer, T. M. Willson, and P. A. Edwards Regulation of Multidrug Resistance-associated Protein 2 (ABCC2) by the Nuclear Receptors Pregnane X Receptor, Farnesoid X-activated Receptor, and Constitutive Androstane Receptor J. Biol. Chem., January 18, 2002; 277(4): 2908 - 2915. [Abstract] [Full Text] [PDF]
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