Bile acids are essential for solubilization and transport of dietary lipids, are the major products of cholesterol catabolism, and are physiological ligands for farnesoid X receptor (FXR), a nuclear receptor that regulates genes involved in lipid metabolism.1 They are also inherently cytotoxic, as physiological imbalance contributes to increased oxidative stress.2,3 Bile acid-controlled signaling pathways are promising novel targets to treat such metabolic diseases as obesity, type II diabetes, hyperlipidemia, and atherosclerosis. Chenodeoxycholic acis (CDCA) is a hydrophobic primary bile acid that activates nuclear receptors involved in cholesterol metabolism.3,4 EC50 concentrations for activation of FXR range from 13-34 μM.5,6 In cells, CDCA also binds to bile acid binding proteins (BABP) with a reported stiochiometery of 1:2.4 CDCA toxicity is linked to increased cellular glutathione levels and increased oxidative stress. Exposure of cells to excess CDCA contributes to liver and intestinal cancers.3
1
Makishima, M., Okamoto, A.Y., Repa, J.J., et al. Identification of a nuclear receptor for bile acids. Science2841362-1365(1999).
2
Barbier, O., Torra, I.P., Sirvent, A., et al. FXR induces the UGT2B4 enzyme in hepatocytes: A potential mechanism of negative feedback control of FXR activity. Gastroenterology1241926-1940(2003).
3
Tan, K.P., Yang, M., and Ito, S. Activation of nuclear factor (erythroid-2 like) factor 2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress. Mol Pharmacol72(5)1380-1390(2007).
4
Eliseo, T., Ragona, L., Catalano, M., et al. Structural and dynamic determinants of ligand binding in the ternary complex of chicken liver bile acid binding protein with two bile salts revealed by NMR. Biochemistry46(44)12557-12567(2007).
5
Urizar, N.L., Liverman, A.B., Dodds, D.T., et al. A natural product that lowers cholesterol as an anatagonist ligand for FXR.. Science2961703-1706(2002).
6
Glickman, J.F., Wu, X., Mercuri, R., et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen7(1)3-10(2002).
Eliseo, T., Ragona, L., Catalano, M., et al. Structural and dynamic determinants of ligand binding in the ternary complex of chicken liver bile acid binding protein with two bile salts revealed by NMR. Biochemistry46(44)12557-12567(2007).
Tan, K.P., Yang, M., and Ito, S. Activation of nuclear factor (erythroid-2 like) factor 2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress. Mol Pharmacol72(5)1380-1390(2007).
Barbier, O., Torra, I.P., Sirvent, A., et al. FXR induces the UGT2B4 enzyme in hepatocytes: A potential mechanism of negative feedback control of FXR activity. Gastroenterology1241926-1940(2003).
Makishima, M., Okamoto, A.Y., Repa, J.J., et al. Identification of a nuclear receptor for bile acids. Science2841362-1365(1999).
Urizar, N.L., Liverman, A.B., Dodds, D.T., et al. A natural product that lowers cholesterol as an anatagonist ligand for FXR.. Science2961703-1706(2002).
Glickman, J.F., Wu, X., Mercuri, R., et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen7(1)3-10(2002).