Role of Mitochondria in Drug-Induced Cholestatic Injury

Clinics in Liver Disease - Tập 12 - Trang 27-51 - 2008
George E.N. Kass1, Shirley C. Price1
1Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK

Tài liệu tham khảo

Nicholls, 2002 Mannella, 2006, Structure and dynamics of the mitochondrial inner membrane cristae, Biochim Biophys Acta, 1763, 542, 10.1016/j.bbamcr.2006.04.006 Rostovtseva, 2005, On the role of VDAC in apoptosis: fact and fiction, J Bioenerg Biomembr, 37, 129, 10.1007/s10863-005-6566-8 Báthori, 2006, Ca2+-dependent control of the permeability properties of the mitochondrial outer membrane and voltage-dependent anion-selective channel (VDAC), J Biol Chem, 281, 17347, 10.1074/jbc.M600906200 Kirichok, 2004, The mitochondrial calcium uniporter is a highly selective ion channel, Nature, 427, 360, 10.1038/nature02246 Rizzuto, 1992, Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin, Nature, 358, 325, 10.1038/358325a0 Rizzuto, 2006, Microdomains of intracellular Ca2+: molecular determinants and functional consequences, Physiol Rev, 86, 369, 10.1152/physrev.00004.2005 Joseph, 2007, IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond, Apoptosis, 12, 951, 10.1007/s10495-007-0719-7 Frazier, 2006, Mitochondrial morphology and distribution in mammalian cells, Biol Chem, 387, 1551, 10.1515/BC.2006.193 Smirnova, 2001, Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells, Mol Biol Cell, 12, 2245, 10.1091/mbc.12.8.2245 James, 2003, hFis1, a novel component of the mammalian mitochondrial fission machinery, J Biol Chem, 278, 36373, 10.1074/jbc.M303758200 Lee, 2007, Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence, J Biol Chem, 282, 22977, 10.1074/jbc.M700679200 Cipolat, 2004, OPA1 requires mitofusin 1 to promote mitochondrial fusion, Proc Natl Acad Sci U S A, 101, 15927, 10.1073/pnas.0407043101 Chen, 2003, Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development, J Cell Biol, 160, 189, 10.1083/jcb.200211046 Zhang, 2007, New insights into mitochondrial fusion, FEBS Lett, 581, 2168, 10.1016/j.febslet.2007.01.095 Delettre, 2001, Nuclear gene OPA1 encoding a mitochondrial dynamin-related problem is mutated in dominant optic atrophy, Invest Ophthalmol Vis Sci, 42, S650 Cipolat, 2006, Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling, Cell, 126, 163, 10.1016/j.cell.2006.06.021 Frezza, 2006, OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion, Cell, 126, 177, 10.1016/j.cell.2006.06.025 Ishihara, 2006, Regulation of mitochondrial morphology through proteolytic cleavage of OPA1, EMBO J, 25, 2966, 10.1038/sj.emboj.7601184 Pellegrini, 2007, A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis, Cell Death Differ, 14, 1275, 10.1038/sj.cdd.4402145 Zuchner, 2004, Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A, Nat Genet, 36, 449, 10.1038/ng1341 Scarpulla, 2006, Nuclear control of respiratory gene expression in mammalian cells, J Cell Biochem, 97, 673, 10.1002/jcb.20743 Savkur, 2005, Coactivation of the human vitamin D receptor by the peroxisome proliferator-activated receptor γ coactivator-1 α, Mol Pharmacol, 68, 511, 10.1124/mol.105.012708 St-Pierre, 2006, Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators, Cell, 127, 397, 10.1016/j.cell.2006.09.024 Mercy, 2005, Mitochondrial biogenesis in mtDNA-depleted cells involves a Ca2+-dependent pathway and a reduced mitochondrial protein import, FEBS J, 272, 5031, 10.1111/j.1742-4658.2005.04913.x Rasbach, 2007, PGC-1 alpha over-expression promotes recovery from mitochondrial dysfunction and cell injury, Biochem Biophys Res Commun, 355, 734, 10.1016/j.bbrc.2007.02.023 Galluzzi, 2007, Cell death modalities: classification and pathophysiological implications, Cell Death Differ, 14, 1237, 10.1038/sj.cdd.4402148 Bossy-Wetzel, 1998, Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization, EMBO J, 17, 37, 10.1093/emboj/17.1.37 Eskes, 1998, Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions, J Cell Biol, 143, 217, 10.1083/jcb.143.1.217 Kuwana, 2002, Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane, Cell, 111, 331, 10.1016/S0092-8674(02)01036-X Hunter, 1979, The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release, Arch Biochem Biophys, 195, 468, 10.1016/0003-9861(79)90373-4 Al-Nasser, 1986, The reversible Ca2+-induced permeabilization of rat liver mitochondria, Biochem J, 239, 19, 10.1042/bj2390019 Halestrap, 1990, Biochem J, 268, 153, 10.1042/bj2680153 Weis, 1994, Further characterization of the events involved in mitochondrial Ca2+ release and pore formation by prooxidants, Biochem Pharmacol, 47, 2147, 10.1016/0006-2952(94)90249-6 Bernardi, 2006, The mitochondrial permeability transition from in vitro artifacts to disease target, FEBS J, 273, 2077, 10.1111/j.1742-4658.2006.05213.x Kass, 1992, Cyclosporin a protects hepatocytes against prooxidant-induced cell killing. A study on the role of mitochondrial Ca2+ cycling in cytotoxicity, Biochem Pharmacol, 44, 1995, 10.1016/0006-2952(92)90102-O Szabo, 1992, The mitochondrial megachannel is the permeability transition pore, J Bioenerg Biomembr, 24, 111, 10.1007/BF00769537 Kroemer, 2007, Mitochondrial membrane permeabilization in cell death, Physiol Rev, 87, 99, 10.1152/physrev.00013.2006 Nakagawa, 2005, Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death, Nature, 434, 652, 10.1038/nature03317 Baines, 2005, Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death, Nature, 434, 658, 10.1038/nature03434 Basso, 2005, Properties of the permeability transition pore in mitochondria devoid of cyclophilin D, J Biol Chem, 280, 18558, 10.1074/jbc.C500089200 Kokoszka, 2004, The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore, Nature, 427, 461, 10.1038/nature02229 Rodic, 2005, DNA methylation is required for silencing of Ant4, an adenine nucleotide translocase selectively expressed in mouse embryonic stem cells and germ cells, Stem Cells, 23, 1314, 10.1634/stemcells.2005-0119 Baines, 2007, Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death, Nat Cell Biol, 9, 550, 10.1038/ncb1575 He, 2002, Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function, FEBS Lett, 512, 1, 10.1016/S0014-5793(01)03314-2 Meinecke, 2006, Tim50 maintains the permeability barrier of the mitochondrial inner membrane, Science, 312, 1523, 10.1126/science.1127628 Brustovetsky, 1996, Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+, Biochemistry, 35, 8483, 10.1021/bi960833v Vergun, 2005, Distinct characteristics of Ca2+-induced depolarization of isolated brain and liver mitochondria, Biochim Biophys Acta, 1709, 127, 10.1016/j.bbabio.2005.07.006 Huser, 1999, Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore, Biochem J, 343, 311, 10.1042/0264-6021:3430311 Kass, 1999, Calcium signaling and cytotoxicity, Environ Health Perspect, 107, 25, 10.1289/ehp.99107s125 Lemasters, 2002, Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy, Antioxid Redox Signal, 4, 769, 10.1089/152308602760598918 Zong, 2006, Necrotic death as a cell fate, Genes Dev, 20, 1, 10.1101/gad.1376506 Holler, 2000, Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule, Nat Immunol, 1, 489, 10.1038/82732 Lin, 2004, Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation, J Biol Chem, 279, 10822, 10.1074/jbc.M313141200 Byun, 2006, Mol Pharmacol, 70, 1099, 10.1124/mol.106.025452 Temkin, 2006, Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis, Mol Cell Biol, 26, 2215, 10.1128/MCB.26.6.2215-2225.2006 Xu, 2006, Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation, J Biol Chem, 281, 8788, 10.1074/jbc.M508135200 Green, 2004, The pathophysiology of mitochondrial cell death, Science, 305, 626, 10.1126/science.1099320 Kim, 2006, Role of mitochondria as the gardens of cell death, Cancer Chemother Pharmacol, 57, 545, 10.1007/s00280-005-0111-7 Li, 1997, Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade, Cell, 91, 479, 10.1016/S0092-8674(00)80434-1 Riedl, 2007, The apoptosome: signalling platform of cell death, Nat Rev Mol Cell Biol, 8, 405, 10.1038/nrm2153 Shiozaki, 2004, Caspases, IAPs and Smac/DIABLO: mechanisms from structural biology, Trends Biochem Sci, 29, 486, 10.1016/j.tibs.2004.07.003 Suzuki, 2001, A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death, Mol Cell, 8, 613, 10.1016/S1097-2765(01)00341-0 Low, 2003, Mitochondrial endonuclease G function in apoptosis and mtDNA metabolism: a historical perspective, Mitochondrion, 2, 225, 10.1016/S1567-7249(02)00104-6 Susin, 1996, Bcl-2 inhibits the mitochondrial release of an apoptogenic protease, J Exp Med, 184, 1331, 10.1084/jem.184.4.1331 Quinn, 1969, Interactions of cytochrome c and [14C]carboxymethylated cytochrome c with monolayers of phosphatidylcholine, phosphatidic acid and cardiolipin, Biochem J, 115, 65, 10.1042/bj1150065 Willis, 2007, Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak, Science, 315, 856, 10.1126/science.1133289 Kim, 2006, Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies, Nat Cell Biol, 8, 1348, 10.1038/ncb1499 Wei, 2001, Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death, Science, 292, 727, 10.1126/science.1059108 Arnoult, 2007, Mitochondrial fragmentation in apoptosis, Trends Cell Biol, 17, 6, 10.1016/j.tcb.2006.11.001 Ott, 2002, Cytochrome c release from mitochondria proceeds by a two-step process, Proc Natl Acad Sci U S A, 99, 1259, 10.1073/pnas.241655498 Basova, 2007, Cardiolipin switch in mitochondria: shutting off the reduction of cytochrome c and turning on the peroxidase activity, Biochemistry, 46, 3423, 10.1021/bi061854k Scorrano, 2002, A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis, Dev Cell, 2, 55, 10.1016/S1534-5807(01)00116-2 Wasiak, 2007, Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death, J Cell Biol, 177, 439, 10.1083/jcb.200610042 Estaquier, 2007, Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis, Cell Death Differ, 14, 1086, 10.1038/sj.cdd.4402107 Parone, 2006, Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis, Mol Cell Biol, 26, 7397, 10.1128/MCB.02282-05 Thorburn, 2004, Death receptor-induced cell killing, Cell Signal, 16, 139, 10.1016/j.cellsig.2003.08.007 Fuentes-Prior, 2004, The protein structures that shape caspase activity, specificity, activation and inhibition, Biochem J, 384, 201, 10.1042/BJ20041142 Yin, 1999, Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis, Nature, 400, 886, 10.1038/23730 Zhao, 2003, Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement, Gastroenterology, 125, 854, 10.1016/S0016-5085(03)01066-7 Levine, 2006, Eating onself and uninvited guests: autophagy-related pathways in cellular defense, Cell, 120, 159, 10.1016/S0092-8674(05)00043-7 Yorimitsu, 2005, Autophagy: molecular machinery for self-eating, Cell Death Differ, 12, 1542, 10.1038/sj.cdd.4401765 Yoshimori, 2007, Autophagy: paying Charon's toll, Cell, 128, 833, 10.1016/j.cell.2007.02.023 Rodriguez-Enriquez, 2004, Role of mitochondrial permeability transition pores in mitochondrial autophagy, Int J Biochem Cell Biol, 36, 2463, 10.1016/j.biocel.2004.04.009 Maiuri, 2007, BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X-L, Autophagy, 3, 374, 10.4161/auto.4237 Li, 2004, The pathology of cholestasis, Semin Liver Dis, 24, 21, 10.1055/s-2004-823099 Pauli-Magnus, 2006, Hepatobiliary transporters and drug-induced cholestasis, Hepatology, 44, 778, 10.1002/hep.21359 Kaplowitz, 2005, Idiosyncratic drug hepatotoxicity, Nat Rev Drug Discov, 4, 489, 10.1038/nrd1750 Plaa, 1976, Intrahepatic cholestasis induced by drugs and chemicals, Pharmacol Rev, 28, 207 Schroder, 1996, Bile acid-induced increase of rat colonic apical membrane fluidity and proton permeability, Z Gastroenterol, 34, 365 Zhao, 1990, Bile salt-induced increases in duodenal brush border membrane proton permeability, fluidity, and fragility, Dig Dis Sci, 35, 589, 10.1007/BF01540406 Elhariri, 1992, The mitigating effects of phosphatidylcholines on bile salt-induced and lysophosphatidylcholine-induced membrane damage, J Pharm Pharmacol, 44, 651, 10.1111/j.2042-7158.1992.tb05487.x Botla, 1995, Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate—a mechanism of UDCA cytoprotection, J Pharmacol Exp Ther, 272, 930 Rolo, 2000, Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy, Toxicol Sci, 57, 177, 10.1093/toxsci/57.1.177 Sokol, 1995, Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids, Gastroenterol, 109, 1249, 10.1016/0016-5085(95)90585-5 Krahenbuhl, 1994, Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria, Hepatology, 19, 471 Guldutuna, 1999, The effect of bile salts and calcium on isolated rat liver mitochondria, Biochim Biophys Acta, 1453, 396, 10.1016/S0925-4439(99)00006-X Rodrigues, 1999, Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation, Cell Death Differ, 6, 842, 10.1038/sj.cdd.4400560 Rodrigues, 1998, A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation, J Clin Invest, 101, 2790, 10.1172/JCI1325 Spivey, 1993, Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes—role of ATP depletion and cytosolic free calcium, J Clin Invest, 92, 17, 10.1172/JCI116546 Yerushalmi, 2001, Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition, Hepatology, 33, 616, 10.1053/jhep.2001.22702 Rodrigues, 2000, Mitochondrial membrane perturbations in cholestasis, J Hepatol, 32, 135, 10.1016/S0168-8278(00)80200-7 Sokol, 1998, Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat, Gastroenterol, 114, 164, 10.1016/S0016-5085(98)70644-4 Krahenbuhl, 1997, Benzoic acid metabolism reflects hepatic mitochondrial function in rats with long-term extrahepatic cholestasis, Hepatology, 25, 278, 10.1053/jhep.1997.v25.pm0009021934 Krahenbuhl, 1994, Mechanisms of impaired hepatic fatty acid metabolism in rats with long-term bile duct ligation, Hepatology, 19, 1272 Krahenbuhl, 1992, Stereological and functional analysis of liver mitochondria from rats with secondary biliary cirrhosis–impaired mitochondrial metabolism and increased mitochondrial content per hepatocyte, Hepatology, 15, 1167, 10.1002/hep.1840150631 Krahenbuhl, 1992, Reduced activity of the electron transport chain in liver mitochondria isolated from rats with secondary biliary cirrhosis, Hepatology, 15, 1160, 10.1002/hep.1840150630 Krahenbuhl, 1998, Reversibility of hepatic mitochondrial damage in rats with long-term cholestasis, J Hepatol, 28, 1000, 10.1016/S0168-8278(98)80349-8 Palmeira, 2003, Histological changes and impairment of liver mitochondrial bioenergetics after long-term treatment with alpha-naphthyl-isothiocyanate (ANIT), Toxicology, 190, 185, 10.1016/S0300-483X(03)00163-X Rolo, 2002, Disruption of mitochondrial calcium homeostasis after chronic alpha-naphthylisothiocyanate administration: relevance for cholestasis, J Investig Med, 50, 193, 10.2310/6650.2002.33433 Rolo, 2003, Mitochondrially mediated synergistic cell killing by bile acids, Biochim Biophys Acta, 1637, 127, 10.1016/S0925-4439(02)00224-7 Sokol, 1993, Evidence for involvement of oxygen-free radicals in bile-acid toxicity to isolated rat hepatocytes, Hepatology, 17, 869, 10.1002/hep.1840170518 Galle, 1990, Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes, Hepatology, 12, 486, 10.1002/hep.1840120307 Gumpricht, 2000, Glutathione status of isolated rat hepatocytes affects bile acid-induced cellular necrosis but not apoptosis, Toxicol Appl Pharmacol, 164, 102, 10.1006/taap.2000.8894 Jones, 1998, Cystatin A expression reduces bile salt-induced apoptosis in a rat hepatoma cell line, Am J Physiol, 38, G723 Jones, 1997, Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C, Am J Physiol, 35, G1109 Kwo, 1995, Nuclear serine-protease activity contributes to bile acid-induced apoptosis in hepatocytes, Am J Physiol, 31, G613 Patel, 1994, Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes, J Clin Invest, 94, 2183, 10.1172/JCI117579 Patel, 1997, Inhibition of bile-salt-induced hepatocyte apoptosis by the antioxidant lazaroid U83836E, Toxicol Appl Pharmacol, 142, 116, 10.1006/taap.1996.8031 Roberts, 1997, Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes, Gastroenterol, 113, 1714, 10.1053/gast.1997.v113.pm9352877 Webster, 2002, cAMP inhibits bile acid-induced apoptosis by blocking caspase activation and cytochrome c release, Am J Physiol, 283, G727 Benz, 1998, Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes, J Hepatol, 28, 99, 10.1016/S0168-8278(98)80208-0 Benz, 1998, Effect of S-adenosylmethionine versus tauroursodeoxycholic acid on bile acid-induced apoptosis and cytolysis in rat hepatocytes, Eur J Clin Invest, 28, 577, 10.1046/j.1365-2362.1998.00315.x Crowley, 2000, The NAD(+) precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate, Cell Death Differ, 7, 314, 10.1038/sj.cdd.4400658 Benz, 2000, Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes, Eur J Clin Invest, 30, 203, 10.1046/j.1365-2362.2000.00615.x Gonzalez, 2000, Glycochenodeoxycholic acid (GCDC) induced hepatocyte apoptosis is associated with early modulation of intracellular PKC activity, Mol Cell Biochem, 207, 19, 10.1023/A:1007021710825 Chieco, 1997, Apoptosis induced in rat hepatocytes by in vivo exposure to taurochenodeoxycholate, Histochem J, 29, 875, 10.1023/A:1026446008712 Chu, 2003, Roles of reactive oxygen species, NF-κB, and peroxiredoxins in glycochenodeoxycholic acid-induced rat hepatocytes death, Pharmacology, 69, 12, 10.1159/000071244 Sodeman, 2000, Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas, Am J Physiol, 278, G992 Faubion, 1999, Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas, J Clin Invest, 103, 137, 10.1172/JCI4765 Qiao, 2001, Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis, Mol Biol Cell, 12, 2629, 10.1091/mbc.12.9.2629 Higuchi, 2001, Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury, J Pharmacol Exp Ther, 299, 866 Graf, 2002, Taurolithocholic acid-3 sulfate apoptosis in a c-Jun N-terminal induces CD95 trafficking and kinase-dependent manner, Gastroenterol, 122, 1411, 10.1053/gast.2002.32976 Reinehr, 2005, Bile salt-induced apoptosis involves NADPH oxidase isoform activation, Gastroenterol, 129, 2009, 10.1053/j.gastro.2005.09.023 Reinehr, 2004, Involvement of the Src family kinase Yes in bile salt-induced apoptosis, Gastroenterol, 127, 1540, 10.1053/j.gastro.2004.08.056 Reinehr, 2003, Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation, Gastroenterol, 125, 839, 10.1016/S0016-5085(03)01055-2 Eberle, 2007, CD95 tyrosine phosphorylation is required for CD95 oligomerization, Apoptosis, 12, 719, 10.1007/s10495-006-0003-2 Becker, 2007, Hydrophobic bile salts trigger ceramide formation through endosomal acidification, Biol Chem, 388, 185, 10.1515/BC.2007.021 Higuchi, 2001, The bile acid glycochenodeoxycholate induces TRAIL-receptor 2/DR5 expression and apoptosis, J Biol Chem, 276, 38610, 10.1074/jbc.M105300200 Higuchi, 2003, Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis, J Biol Chem, 278, 454, 10.1074/jbc.M209387200 Wang, 2005, Reversibility of caspase activation and its role during glycochenodeoxycholate-induced hepatocyte apoptosis, J Biol Chem, 280, 23490, 10.1074/jbc.M411607200 Qiao, 2002, Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes, Hepatology, 35, 779, 10.1053/jhep.2002.32533 Gumpricht, 2002, Nitric oxide ameliorates hydrophobic bile acid-induced apoptosis in isolated rat hepatocytes by non-mitochondrial pathways, J Biol Chem, 277, 25823, 10.1074/jbc.M112305200 Hatano, 2000, The mitochondrial permeability transition augments Fas-induced apoptosis in mouse hepatocytes, J Biol Chem, 275, 11814, 10.1074/jbc.275.16.11814 Schoemaker, 2003, Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation, J Hepatol, 39, 153, 10.1016/S0168-8278(03)00214-9 Tsuchiya, 2006, Involvement of endoplasmic reticulum in glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes, Toxicol Lett, 166, 140, 10.1016/j.toxlet.2006.06.006 Canbay, 2003, Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis, J Clin Invest, 112, 152, 10.1172/JCI200317740 Fickert, 2005, Oncosis represents the main type of cell death in mouse models of cholestasis, J Hepatol, 42, 378, 10.1016/j.jhep.2004.10.016 Gujral, 2004, Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation, Hepatology, 40, 998, 10.1002/hep.1840400431 Guicciardi, 2005, Cholestatic hepatocellular injury: what do we know and how should we proceed, J Hepatol, 42, 297, 10.1016/j.jhep.2004.12.014 Miyoshi, 1999, Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas, Gastroenterol, 117, 669, 10.1016/S0016-5085(99)70461-0 Canbay, 2004, The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse, J Hepatol, 40, 9, 10.1016/S0168-8278(04)90022-0 El-Hassan, 2003, Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid and caspases, Toxicol Appl Pharmacol, 191, 118, 10.1016/S0041-008X(03)00240-0 Kass, 2006, Mitochondrial involvement in drug-induced hepatic injury, Chem Biol Interact, 163, 145, 10.1016/j.cbi.2006.06.007 Kobak, 2005, Increased susceptibility of fat-laden Zucker-rat hepatocytes to bile acid-induced oncotic necrosis: an in vitro model of steatocholestasis, J Lab Clin Med, 145, 247, 10.1016/j.lab.2004.12.007 Rust, 2000, The bile acid taurochenodexoycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade, J Biol Chem, 275, 20210, 10.1074/jbc.M909992199 Rust, 2005, Phosphatidylinositol 3-kinase-dependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers, Am J Physiol, 289, G88 Takikawa, 2001, The bile acid-activated phosphatidylinositol 3-kinase pathway inhibits Fas apoptosis upstream of Bid in rodent hepatocytes, Gastroenterol, 120, 1810, 10.1053/gast.2001.24835 Azzaroli, 2002, Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes, Hepatology, 36, 49, 10.1053/jhep.2002.34511 Hirano, 2006, Chenodeoxycholic acid and taurochenodexycholic acid induce anti-apoptotic cIAP-1 expression in human hepatocytes, J Gastroenterol Hepatol, 21, 1807, 10.1111/j.1440-1746.2006.04363.x Gupta, 2000, Regulation of multidrug resistance 2 P-glycoprotein expression by bile salts in rats and in primary cultures of rat hepatocytes, Hepatology, 32, 341, 10.1053/jhep.2000.9605 Kurosawa, 1997, Hepatocytes in the bile duct-ligated rat express Bcl-2, Am J Physiol, 35, G1587 Koga, 1997, Nuclear DNA fragmentation and expression of Bcl-2 in primary biliary cirrhosis, Hepatology, 25, 1077, 10.1002/hep.510250505 Vogel, 2006, Sustained phosphorylation of Bid is a marker for resistance to Fas-induced apoptosis during chronic liver diseases, Gastroenterol, 130, 104, 10.1053/j.gastro.2005.10.012 Miyoshi, 2001, NF-kappa B is activated in cholestasis and functions to reduce liver injury, Am J Pathol, 158, 967, 10.1016/S0002-9440(10)64043-6 Lieser, 1998, Cholestasis confers resistance to the rat liver mitochondrial permeability transition, Gastroenterol, 115, 693, 10.1016/S0016-5085(98)70149-0 Forestier, 1997, Hepatic mitochondrial proliferation in rats with secondary biliary cirrhosis: time course and mechanisms, Hepatology, 26, 386, 10.1002/hep.510260219 Gehring, 2006, Kupffer cells abrogate cholestatic liver injury in mice, Gastroenterol, 130, 810, 10.1053/j.gastro.2005.11.015 Heathcote, 2007, Diagnosis and management of cholestatic liver disease, Clin Gastroenterol Hepatol, 5, 776, 10.1016/j.cgh.2007.05.008 Krahenbuhl, 1994, Ursodeoxycholate protects oxidative mitochondrial metabolism from bile acid toxicity—dose-response study in isolated rat liver mitochondria, Hepatology, 20, 1595, 10.1002/hep.1840200632 Rodrigues, 2003, Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome c release in isolated mitochondria, Biochemistry, 42, 3070, 10.1021/bi026979d Serviddio, 2004, Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress, Hepatology, 39, 711, 10.1002/hep.20101 Schoemaker, 2004, Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways, Hepatology, 39, 1563, 10.1002/hep.20246 Sola, 2005, Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-beta 1-induced apoptosis in rat hepatocytes, Hepatology, 42, 925, 10.1002/hep.20870 Nowak, 2005, Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats, Transpl Int, 17, 804, 10.1111/j.1432-2277.2004.tb00514.x Rodrigues, 2003, Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats, Proc Natl Acad Sci U S A, 100, 6087, 10.1073/pnas.1031632100 Ducluzeau, 1999, Depletion of mitochondrial DNA associated with infantile cholestasis and progressive liver fibrosis, J Hepatol, 30, 149, 10.1016/S0168-8278(99)80019-1 Lee, 2007, Mitochondrial hepatopathies: advances in genetics and pathogenesis, Hepatology, 45, 1555, 10.1002/hep.21710 Mandel, 2001, The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies, Hepatology, 34, 776, 10.1053/jhep.2001.27664