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Journal of Lipid Research, Vol. 50, 1721-1734, September 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Bile Acids

Bile acids: regulation of apoptosis by ursodeoxycholic acid

Joana D. Amaral^*, Ricardo J. S. Viana^*, Rita M. Ramalho^*, Clifford J. Steer and Cecília M. P. Rodrigues^1,*

^* Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
Departments of Medicine, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN

¹ To whom correspondence should be addressed. e-mail: cmprodrigues{at}ff.ul.pt

Bile acids are a group of molecular species of acidic steroids with peculiar physical-chemical and biological characteristics. At high concentrations they become toxic to mammalian cells, and their presence is pertinent in the pathogenesis of several liver diseases and colon cancer. Bile acid cytoxicity has been related to membrane damage, but also to nondetergent effects, such as oxidative stress and apoptosis. Strikingly, hydrophilic ursodeoxycholic acid (UDCA), and its taurine-conjugated form (TUDCA), show profound cytoprotective properties. Indeed, these molecules have been described as potent inhibitors of classic pathways of apoptosis, although their precise mode of action remains to be clarified. UDCA, originally used for cholesterol gallstone dissolution, is currently considered the first choice therapy for several forms of cholestatic syndromes. However, the beneficial effects of both UDCA and TUDCA have been tested in other experimental pathological conditions with deregulated levels of apoptosis, including neurological disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Here, we review the role of bile acids in modulating the apoptosis process, emphasizing the anti-apoptotic effects of UDCA and TUDCA, as well as their potential use as novel and alternate therapeutic agents for the treatment of apoptosis-related diseases.

Supplementary key words Bcl-2 family • cell death • liver • neuroprotection • nuclear steroid receptors

Abbreviations: Aβ, amyloid β; AP-1, activating protein-1; CDK, cyclin-dependent kinase; C/EBPβ, CCAAT enhancer binding protein β; CREB, cyclic AMP-response element binding protein; CYP7A1, cholesterol 7-hydroxylase; CYP8B1, cholesterol 12-hydrolase; DCA, deoxycholic acid; ER, endoplasmic reticulum; ERK, extracellular-regulated kinase; FADD, Fas-associated death domain; FGF19, fibroblast growth factor intestine 19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; GC, glucocorticoid; GCDCA, glycochenodeoxycholic acid; GR, glucocorticoid receptor; JNK, c-Jun NH₂-terminal kinase; LBD, ligand binding domain; LRH-1, liver receptor homolog-1; MAPK, mitogen-activated protein kinase; MR, mineralcorticoid receptor; NF-B, nuclear factor B; NSR, nuclear steroid receptor; PC12, pheochromocytoma; PI3K, phosphatidylinositol 3-kinase; pRb, retinoblastoma protein; PXR, pregnane X receptor; ROS, reactive oxygen species; RSK, ribosomal S6 kinase; SHP, small heterodimer partner; TGF-β1, transforming growth factor β1; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis inducing ligand; TTR, transthyretin; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid

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