Abstract
If the bile acids reach to pathological concentrations due to cholestasis, accumulation of hydrophobic bile acids within the hepatocyte may result in cell death. Thus, hydrophobic bile acids induce apoptosis in hepatocytes, while hydrophilic bile acids increase intracellular adenosine 3′,5′-monophosphate (cAMP) levels and activate mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways to protect hepatocytes from apoptosis.
Two apoptotic pathways have been described in bile acids-induced death. Both are controlled by multiple protein kinase signaling pathways. In mitochondria-controlled pathway, caspase-8 is activated with death domain-independent manner, whereas, Fas-dependent classical pathway involves ligand-independent oligomerization of Fas.
Hydrophobic bile acids dose-dependently upregulate the inflammatory response by further stimulating production of inflammatory cytokines. Death receptor-mediated apoptosis is regulated at the cell surface by the receptor expression, at the death-inducing signaling complex (DISC) by expression of procaspase-8, the death receptors Fas-associated death domain (FADD), and cellular FADD-like interleukin 1-beta (IL-1β)–converting enzyme (FLICE) inhibitory protein (cFLIP). Bile acids prevent cFLIP recruitment to the DISC and thereby enhance initiator caspase activation and lead to cholestatic apoptosis. At mitochondria, the expression of B-cell leukemia/lymphoma-2 (Bcl-2) family proteins contribute to apoptosis by regulating mitochondrial cytochrome c release via Bcl-2, Bcl-2 homology 3 (BH3) interacting domain death agonist (Bid), or Bcl-2 associated protein x (Bax). Fas receptor CD95 activation by hydrophobic bile acids is initiated by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) signaling. However, activation of necroptosis by ligands of death receptors requires the kinase activity of receptor interacting protein1 (RIP1), which mediates the activation of RIP3 and mixed lineage kinase domain-like protein (MLKL). In this chapter, mainly the effect of protein kinases signal transduction on the mechanisms of hydrophobic bile acids-induced inflammation, apoptosis, necroptosis and necrosis are discussed.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Afonso MB, Rodrigues PM, Simão AL, Ofengeim D, Carvalho T, Amaral JD, Gaspar MM, Cortez-Pinto H, Castro RE, Yuan J, Rodrigues CMP. Activation of necroptosis in human and experimental cholestasis. Cell Death Dis. 2016;7:e2390. https://doi.org/10.1038/cddis.2016.280.
Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137–63. https://doi.org/10.1146/annurev.biochem.75.103004.142702.
Allen K, Kim ND, Moon J-O, Copple BL. Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling. Toxicol Appl Pharmacol. 2010;243:63–7. https://doi.org/10.1016/j.taap.2009.11.013.
Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol. 2011;178:175–86. https://doi.org/10.1016/j.ajpath.2010.11.026.
Alpini G, Glaser SS, Rodgers R, Phinizy JL, Robertson WE, Lasater J, Caligiuri A, Tretjak Z, LeSage GD. Functional expression of the apical Na+-dependent bile acid transporter in large but not small rat cholangiocytes. Gastroenterology. 1997;113:1734–40. https://doi.org/10.1053/gast.1997.v113.pm9352879.
Alpini G, Ueno Y, Glaser SS, Marzioni M, Phinizy JL, Francis H, Lesage G. Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes. Hepatology. 2001;34:868–76. https://doi.org/10.1053/jhep.2001.28884.
Alpini G, Baiocchi L, Glaser S, Ueno Y, Marzioni M, Francis H, Phinizy JL, Angelico M, Lesage G. Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha. Hepatology. 2002a;35:1041–52. https://doi.org/10.1053/jhep.2002.32712.
Alpini G, Glaser S, Alvaro D, Ueno Y, Marzioni M, Francis H, Baiocchi L, Stati T, Barbaro B, Phinizy JL, Mauldin J, Lesage G. Bile acid depletion and repletion regulate cholangiocyte growth and secretion by a phosphatidylinositol 3-kinase-dependent pathway in rats. Gastroenterology. 2002b;123:1226–37. https://doi.org/10.1053/gast.2002.36055.
Alpini G, Kanno N, Phinizy JL, Glaser S, Francis H, Taffetani S, LeSage G. Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca2+-, PKC-, and MAPK-dependent pathways. Am J Physiol Gastrointest Liver Physiol. 2004;286:G973–82. https://doi.org/10.1152/ajpgi.00270.2003.
Alrefai WA, Gill RK. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res. 2007;24:1803–23. https://doi.org/10.1007/s11095-007-9289-1.
Amaral JD, Castro RE, Solá S, Steer CJ, Rodrigues CMP. p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis. J Biol Chem. 2007;282:34250–9. https://doi.org/10.1074/jbc.M704075200.
Amaral JD, Viana RJS, Ramalho RM, Steer CJ, Rodrigues CMP. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. 2009;50:1721–34. https://doi.org/10.1194/jlr.R900011-JLR200.
Araki Y, Fujiyama Y, Andoh A, Nakamura F, Shimada M, Takaya H, Bamba T. Hydrophilic and hydrophobic bile acids exhibit different cytotoxicities through cytolysis, interleukin-8 synthesis and apoptosis in the intestinal epithelial cell lines. IEC-6 and Caco-2 cells. Scand J Gastroenterol. 2001;36:533–9. https://doi.org/10.1080/003655201750153430.
Araki Y, Andoh A, Bamba H, Yoshikawa K, Doi H, Komai Y, Higuchi A, Fujiyama Y. The cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids in intestinal cell lines IEC-6 and Caco-2. Oncol Rep. 2003;10:1931–6.
Arisawa S, Ishida K, Kameyama N, Ueyama J, Hattori A, Tatsumi Y, Hayashi H, Yano M, Hayashi K, Katano Y, Goto H, Takagi K, Wakusawa S. Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells. Biochem Pharmacol. 2009;77:858–66. https://doi.org/10.1016/j.bcp.2008.11.012.
Asamoto Y, Tazuma S, Ochi H, Chayama K, Suzuki H. Bile-salt hydrophobicity is a key factor regulating rat liver plasma-membrane communication: relation to bilayer structure, fluidity and transporter expression and function. Biochem J. 2001;359:605–10. https://doi.org/10.1042/0264-6021:3590605.
Attili AF, Angelico M, Cantafora A, Alvaro D, Capocaccia L. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses. 1986;19:57–69. https://doi.org/10.1016/0306-9877(86)90137-4.
Baghdasaryan A, Chiba P, Trauner M. Clinical application of transcriptional activators of bile salt transporters. Mol Asp Med. 2014;37:57–76. https://doi.org/10.1016/j.mam.2013.12.001.
Baiocchi L, Zhou T, Liangpunsakul S, Lenci I, Santopaolo F, Meng F, Kennedy L, Glaser S, Francis H, Alpini G. Dual role of bile acids on the biliary epithelium: friend or foe? Int J Mol Sci. 2019;20:1869. https://doi.org/10.3390/ijms20081869.
Ballatori N, Li N, Fang F, Boyer JL, Christian WV, Hammond CL. OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci (Landmark Ed). 2009;14:2829–44. https://doi.org/10.2741/3416.
Barnes S, Gollan JL, Billing BH. The role of tubular reabsorption in the renal excretion of bile acids. Biochem J. 1977;166:65–73. https://doi.org/10.1042/bj1660065.
Becker S, Reinehr R, Graf D, vom Dahl S, Häussinger D. Hydrophobic bile salts induce hepatocyte shrinkage via NADPH oxidase activation. Cell Physiol Biochem. 2007;19:89–98. https://doi.org/10.1159/000099197.
Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science. 1998;282:290–3. https://doi.org/10.1126/science.282.5387.290.
Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology. 1998;28:1449–53. https://doi.org/10.1002/hep.510280601.
Boaglio AC, Zucchetti AE, Sánchez Pozzi EJ, Pellegrino JM, Ochoa JE, Mottino AD, Vore M, Crocenzi FA, Roma MG. Phosphoinositide 3-kinase/protein kinase B signaling pathway is involved in estradiol 17β-D-glucuronide-induced cholestasis: complementarity with classical protein kinase C. Hepatology. 2010;52:1465–76. https://doi.org/10.1002/hep.23846.
Borst P, Evers R, Kool M, Wijnholds J. The multidrug resistance protein family. Biochim Biophys Acta. 1999;1461:347–57. https://doi.org/10.1016/s0005-2736(99)00167-4.
Botla R, Spivey JR, Aguilar H, Bronk SF, Gores GJ. Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection. J Pharmacol Exp Ther. 1995;272:930–8.
Boyer JL. New concepts of mechanisms of hepatocyte bile formation. Physiol Rev. 1980;60:303–26. https://doi.org/10.1152/physrev.1980.60.2.303.
Cadoret A, Rey C, Wendum D, Elriz K, Tronche F, Holzenberger M, Housset C. IGF-1R contributes to stress-induced hepatocellular damage in experimental cholestasis. Am J Pathol. 2009;175:627–35. https://doi.org/10.2353/ajpath.2009.081081.
Cai Z, Jitkaew S, Zhao J, Chiang H-C, Choksi S, Liu J, Ward Y, Wu L-G, Liu Z-G. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2014;16:55–65. https://doi.org/10.1038/ncb2883.
Cai S-Y, Ouyang X, Chen Y, Soroka CJ, Wang J, Mennone A, Wang Y, Mehal WZ, Jain D, Boyer JL. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight. 2017;2:e90780. https://doi.org/10.1172/jci.insight.90780.
Cao R, Cronk ZX, Zha W, Sun L, Wang X, Fang Y, Studer E, Zhou H, Pandak WM, Dent P, Gil G, Hylemon PB. Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway. J Lipid Res. 2010;51:2234–44. https://doi.org/10.1194/jlr.M004929.
Castro RE, Rodrigues CMP. Cell death and microRNAs in cholestatic liver diseases: update on potential therapeutic applications. Curr Drug Targets. 2017;18:921–31. https://doi.org/10.2174/1389450116666151019102358.
Chiang JYL. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol. 2004;40:539–51. https://doi.org/10.1016/j.jhep.2003.11.006.
Chiang JYL. Bile acid metabolism and signaling. Compr Physiol. 2013;3:1191–212. https://doi.org/10.1002/cphy.c120023.
Christie DM, Dawson PA, Thevananther S, Shneider BL. Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum. Am J Phys. 1996;271:G377–85. https://doi.org/10.1152/ajpgi.1996.271.2.G377.
Cullen KA, McCool J, Anwer MS, Webster CRL. Activation of cAMP-guanine exchange factor confers PKA-independent protection from hepatocyte apoptosis. Am J Physiol Gastrointest Liver Physiol. 2004;287:G334–43. https://doi.org/10.1152/ajpgi.00517.2003.
Dent P, Fang Y, Gupta S, Studer E, Mitchell C, Spiegel S, Hylemon PB. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology. 2005;42:1291–9. https://doi.org/10.1002/hep.20942.
Duane WC, Javitt NB. 27-hydroxycholesterol: production rates in normal human subjects. J Lipid Res. 1999;40:1194–9.
Duane WC, Xiong W, Wolvers J. Effects of bile acids on expression of the human apical sodium dependent bile acid transporter gene. Biochim Biophys Acta. 2007;1771:1380–8. https://doi.org/10.1016/j.bbalip.2007.09.003.
Fang Y, Han SI, Mitchell C, Gupta S, Studer E, Grant S, Hylemon PB, Dent P. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology. 2004;40:961–71. https://doi.org/10.1002/hep.20385.
Fang Y, Studer E, Mitchell C, Grant S, Pandak WM, Hylemon PB, Dent P. Conjugated bile acids regulate hepatocyte glycogen synthase activity in vitro and in vivo via Galphai signaling. Mol Pharmacol. 2007;71:1122–8. https://doi.org/10.1124/mol.106.032060.
Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann SH, Gores GJ. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest. 1999;103:137–45. https://doi.org/10.1172/JCI4765.
Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Häcker G, Leverkus M. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43:449–63. https://doi.org/10.1016/j.molcel.2011.06.011.
Fu D, Wakabayashi Y, Ido Y, Lippincott-Schwartz J, Arias IM. Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1. J Cell Sci. 2010;123:3294–302. https://doi.org/10.1242/jcs.068098.
Fu D, Wakabayashi Y, Lippincott-Schwartz J, Arias IM. Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway. Proc Natl Acad Sci U S A. 2011;108:1403–8. https://doi.org/10.1073/pnas.1018376108.
García-Cañaveras JC, Donato MT, Castell JV, Lahoz A. Targeted profiling of circulating and hepatic bile acids in human, mouse, and rat using a UPLC-MRM-MS-validated method. J Lipid Res. 2012;53:2231–41. https://doi.org/10.1194/jlr.D028803.
Gehrke N, Nagel M, Straub BK, Wörns MA, Schuchmann M, Galle PR, Schattenberg JM. Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation. Am J Physiol Gastrointest Liver Physiol. 2018;314:G319–33. https://doi.org/10.1152/ajpgi.00097.2017.
Gomez-Santos L, Luka Z, Wagner C, Fernandez-Alvarez S, Lu SC, Mato JM, Martinez-Chantar ML, Beraza N. Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase. Hepatology. 2012;56:747–59. https://doi.org/10.1002/hep.25694.
Gong Z, Zhou J, Zhao S, Tian C, Wang P, Xu C, Chen Y, Cai W, Wu J. Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget. 2016;7:83951–63. https://doi.org/10.18632/oncotarget.13796.
Gonzalez FJ. Nuclear receptor control of enterohepatic circulation. Compr Physiol. 2012;2:2811–28. https://doi.org/10.1002/cphy.c120007.
Graf D, Kurz AK, Fischer R, Reinehr R, Häussinger D. Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner. Gastroenterology. 2002;122:1411–27. https://doi.org/10.1053/gast.2002.32976.
Guo C, Chen W-D, Wang Y-D. TGR5, not only a metabolic regulator. Front Physiol. 2016a;7:646. https://doi.org/10.3389/fphys.2016.00646.
Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, Zheng M, Zhang X, Xia D, Ke Y, Lu L, Wang D. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016b;45:802–16. https://doi.org/10.1016/j.immuni.2016.09.008.
Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest. 1994;93:1326–31. https://doi.org/10.1172/JCI117091.
Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science. 2009;325:1254–7. https://doi.org/10.1126/science.1176709.
Hao H, Cao L, Jiang C, Che Y, Zhang S, Takahashi S, Wang G, Gonzalez FJ. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab. 2017;25:856–867.e5. https://doi.org/10.1016/j.cmet.2017.03.007.
Hardison WG, Grundy SM. Effect of bile acid conjugation pattern on bile acid metabolism in normal humans. Gastroenterology. 1983;84:617–20.
Häussinger D, Schmitt M, Weiergräber O, Kubitz R. Short-term regulation of canalicular transport. Semin Liver Dis. 2000;20:307–21. https://doi.org/10.1055/s-2000-9386.
He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100–11. https://doi.org/10.1016/j.cell.2009.05.021.
Higuchi H, Gores GJ. Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. Am J Physiol Gastrointest Liver Physiol. 2003;284:G734–8. https://doi.org/10.1152/ajpgi.00491.2002.
Higuchi H, Bronk SF, Takikawa Y, Werneburg N, Takimoto R, El-Deiry W, Gores GJ. The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. J Biol Chem. 2001;276:38610–8. https://doi.org/10.1074/jbc.M105300200.
Higuchi H, Yoon J-H, Grambihler A, Werneburg N, Bronk SF, Gores GJ. Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis. J Biol Chem. 2003;278:454–61. https://doi.org/10.1074/jbc.M209387200.
Hofmann AF. Bile acids: the good, the bad, and the ugly. News Physiol Sci. 1999;14:24–9. https://doi.org/10.1152/physiologyonline.1999.14.1.24.
Hofmann AF. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab Rev. 2004;36:703–22. https://doi.org/10.1081/dmr-200033475.
Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008;65:2461–83. https://doi.org/10.1007/s00018-008-7568-6.
Hohenester S, Gates A, Wimmer R, Beuers U, Anwer MS, Rust C, Webster CRL. Phosphatidylinositol-3-kinase p110γ contributes to bile salt-induced apoptosis in primary rat hepatocytes and human hepatoma cells. J Hepatol. 2010;53:918–26. https://doi.org/10.1016/j.jhep.2010.05.015.
Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17:1581–91. https://doi.org/10.1101/gad.1083503.
Homolya L, Fu D, Sengupta P, Jarnik M, Gillet J-P, Vitale-Cross L, Gutkind JS, Lippincott-Schwartz J, Arias IM. LKB1/AMPK and PKA control ABCB11 trafficking and polarization in hepatocytes. PLoS One. 2014;9:e91921. https://doi.org/10.1371/journal.pone.0091921.
Humbert L, Maubert MA, Wolf C, Duboc H, Mahé M, Farabos D, Seksik P, Mallet JM, Trugnan G, Masliah J, Rainteau D. Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;899:135–45. https://doi.org/10.1016/j.jchromb.2012.05.015.
Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res. 2009;50:1509–20. https://doi.org/10.1194/jlr.R900007-JLR200.
Ikeda Y, Morita S-Y, Terada T. Cholesterol attenuates cytoprotective effects of phosphatidylcholine against bile salts. Sci Rep. 2017;7:306. https://doi.org/10.1038/s41598-017-00476-2.
Johnston A, Ponzetti K, Anwer MS, Webster CRL. cAMP-guanine exchange factor protection from bile acid-induced hepatocyte apoptosis involves glycogen synthase kinase regulation of c-Jun NH2-terminal kinase. Am J Physiol Gastrointest Liver Physiol. 2011;301:G385–400. https://doi.org/10.1152/ajpgi.00430.2010.
Karimian G, Buist-Homan M, Schmidt M, Tietge UJF, de Boer JF, Klappe K, Kok JW, Combettes L, Tordjmann T, Faber KN, Moshage H. Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile salt-induced apoptosis. Biochim Biophys Acta. 2013;1832:1922–9. https://doi.org/10.1016/j.bbadis.2013.06.011.
Keitel V, Häussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol. 2012;36:412–9. https://doi.org/10.1016/j.clinre.2012.03.008.
Keitel V, Häussinger D. TGR5 in cholangiocytes. Curr Opin Gastroenterol. 2013;29:299–304. https://doi.org/10.1097/MOG.0b013e32835f3f14.
Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116. https://doi.org/10.1146/annurev.pharmtox.46.120604.141046.
Kim TH, Zhao Y, Barber MJ, Kuharsky DK, Yin XM. Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J Biol Chem. 2000;275:39474–81. https://doi.org/10.1074/jbc.M003370200.
Kim ND, Moon J-O, Slitt AL, Copple BL. Early growth response factor-1 is critical for cholestatic liver injury. Toxicol Sci. 2006;90:586–95. https://doi.org/10.1093/toxsci/kfj111.
Kim S, Han SY, Yu KS, Han D, Ahn H-J, Jo J-E, Kim J-H, Shin J, Park H-W. Impaired autophagy promotes bile acid-induced hepatic injury and accumulation of ubiquitinated proteins. Biochem Biophys Res Commun. 2018;495:1541–7. https://doi.org/10.1016/j.bbrc.2017.11.202.
Kip N-S, Lazaridis K-N, Masyuk A-I, Splinter P-L, Huebert R-C, LaRusso N-F. Differential expression of cholangiocyte and ileal bile acid transporters following bile acid supplementation and depletion. World J Gastroenterol. 2004;10:1440–6. https://doi.org/10.3748/wjg.v10.i10.1440.
Kipp H, Arias IM. Newly synthesized canalicular ABC transporters are directly targeted from the Golgi to the hepatocyte apical domain in rat liver. J Biol Chem. 2000;275:15917–25. https://doi.org/10.1074/jbc.M909875199.
Kipp H, Arias IM. Trafficking of canalicular ABC transporters in hepatocytes. Annu Rev Physiol. 2002;64:595–608. https://doi.org/10.1146/annurev.physiol.64.081501.155793.
Kluwe J, Pradere J-P, Gwak G-Y, Mencin A, De Minicis S, Osterreicher CH, Colmenero J, Bataller R, Schwabe RF. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology. 2010;138:347–59. https://doi.org/10.1053/j.gastro.2009.09.015.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 2000;7:1166–73. https://doi.org/10.1038/sj.cdd.4400783.
Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–72. https://doi.org/10.1053/j.gastro.2012.09.008.
Kubitz R, Sütfels G, Kühlkamp T, Kölling R, Häussinger D. Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology. 2004;126:541–53. https://doi.org/10.1053/j.gastro.2003.11.003.
Kubitz R, Dröge C, Stindt J, Weissenberger K, Häussinger D. The bile salt export pump (BSEP) in health and disease. Clin Res Hepatol Gastroenterol. 2012;36:536–53. https://doi.org/10.1016/j.clinre.2012.06.006.
Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ. Hepatic transport of bile salts. Semin Liver Dis. 2000;20:273–92. https://doi.org/10.1055/s-2000-9426.
Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001;120:525–33. https://doi.org/10.1053/gast.2001.21176.
Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology. 2004;126:322–42. https://doi.org/10.1053/j.gastro.2003.06.005.
Kurz AK, Graf D, Schmitt M, Vom Dahl S, Häussinger D. Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats. Gastroenterology. 2001;121:407–19. https://doi.org/10.1053/gast.2001.26262.
Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL. Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Physiol Cell Physiol. 2007;293:C1709–16. https://doi.org/10.1152/ajpcell.00327.2007.
Lazaridis KN, Pham L, Tietz P, Marinelli RA, deGroen PC, Levine S, Dawson PA, LaRusso NF. Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest. 1997;100:2714–21. https://doi.org/10.1172/JCI119816.
Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid “mechanisms of action and clinical use in hepatobiliary disorders”. J Hepatol. 2001;35:134–46. https://doi.org/10.1016/s0168-8278(01)00092-7.
Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta. 1998;1366:177–96. https://doi.org/10.1016/s0005-2728(98)00112-1.
LeSage G, Glaser S, Alpini G. Regulation of cholangiocyte proliferation. Liver. 2001;21:73–80. https://doi.org/10.1034/j.1600-0676.2001.021002073.x.
Li T, Jahan A, Chiang JYL. Bile acids and cytokines inhibit the human cholesterol 7 alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells. Hepatology. 2006a;43:1202–10. https://doi.org/10.1002/hep.21183.
Li T, Kong X, Owsley E, Ellis E, Strom S, Chiang JYL. Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c. J Biol Chem. 2006b;281:28745–54. https://doi.org/10.1074/jbc.M605815200.
Li T, Chanda D, Zhang Y, Choi H-S, Chiang JYL. Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. J Lipid Res. 2010;51:832–42. https://doi.org/10.1194/jlr.M002782.
Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao Y-S, Damko E, Moquin D, Walz T, McDermott A, Chan FK-M, Wu H. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012a;150:339–50. https://doi.org/10.1016/j.cell.2012.06.019.
Li T, Francl JM, Boehme S, Ochoa A, Zhang Y, Klaassen CD, Erickson SK, Chiang JYL. Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity. J Biol Chem. 2012b;287:1861–73. https://doi.org/10.1074/jbc.M111.305789.
Li M, Cai S-Y, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver. Mol Asp Med. 2017;56:45–53. https://doi.org/10.1016/j.mam.2017.06.001.
Liedtke C, Bangen J-M, Freimuth J, Beraza N, Lambertz D, Cubero FJ, Hatting M, Karlmark KR, Streetz KL, Krombach GA, Tacke F, Gassler N, Riethmacher D, Trautwein C. Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology. 2011;141:2176–87. https://doi.org/10.1053/j.gastro.2011.08.037.
Lou G, Ma X, Fu X, Meng Z, Zhang W, Wang Y-D, Van Ness C, Yu D, Xu R, Huang W. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS One. 2014;9:e93567. https://doi.org/10.1371/journal.pone.0093567.
Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology. 2014;147:765–783.e4. https://doi.org/10.1053/j.gastro.2014.07.018.
Maceyka M, Payne SG, Milstien S, Spiegel S. Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. Biochim Biophys Acta. 2002;1585:193–201. https://doi.org/10.1016/s1388-1981(02)00341-4.
Maceyka M, Sankala H, Hait NC, Le Stunff H, Liu H, Toman R, Collier C, Zhang M, Satin LS, Merrill AH, Milstien S, Spiegel S. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem. 2005;280:37118–29. https://doi.org/10.1074/jbc.M502207200.
Maher JJ. What doesn’t kill you makes you stronger: how hepatocytes survive prolonged cholestasis. Hepatology. 2004;39:1141–3. https://doi.org/10.1002/hep.20134.
Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–5. https://doi.org/10.1126/science.284.5418.1362.
Malhi H, Guicciardi ME, Gores GJ. Hepatocyte death: a clear and present danger. Physiol Rev. 2010;90:1165–94. https://doi.org/10.1152/physrev.00061.2009.
Masyuk AI, Huang BQ, Radtke BN, Gajdos GB, Splinter PL, Masyuk TV, Gradilone SA, LaRusso NF. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am J Physiol Gastrointest Liver Physiol. 2013;304:G1013–24. https://doi.org/10.1152/ajpgi.00383.2012.
Mayati A, Moreau A, Le Vée M, Stieger B, Denizot C, Parmentier Y, Fardel O. Protein kinases C-mediated regulations of drug transporter activity, localization and expression. Int J Mol Sci. 2017;18:764. https://doi.org/10.3390/ijms18040764.
McConkey M, Gillin H, Webster CRL, Anwer MS. Cross-talk between protein kinases Czeta and B in cyclic AMP-mediated sodium taurocholate co-transporting polypeptide translocation in hepatocytes. J Biol Chem. 2004;279:20882–8. https://doi.org/10.1074/jbc.M309988200.
Meier PJ, Stieger B. Bile salt transporters. Annu Rev Physiol. 2002;64:635–61. https://doi.org/10.1146/annurev.physiol.64.082201.100300.
Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, Österreicher CH, Stickel F, Ley K, Brenner DA, Kisseleva T. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012;143:765–776.e3. https://doi.org/10.1053/j.gastro.2012.05.049.
Misra S, Ujházy P, Gatmaitan Z, Varticovski L, Arias IM. The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver. J Biol Chem. 1998;273:26638–44. https://doi.org/10.1074/jbc.273.41.26638.
Misra S, Varticovski L, Arias IM. Mechanisms by which cAMP increases bile acid secretion in rat liver and canalicular membrane vesicles. Am J Physiol Gastrointest Liver Physiol. 2003;285:G316–24. https://doi.org/10.1152/ajpgi.00048.2003.
Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18:516–23. https://doi.org/10.1016/j.ceb.2006.08.011.
Miyoshi H, Rust C, Roberts PJ, Burgart LJ, Gores GJ. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas. Gastroenterology. 1999;117:669–77. https://doi.org/10.1016/s0016-5085(99)70461-0.
Morita S, Ikeda N, Horikami M, Soda K, Ishihara K, Teraoka R, Terada T, Kitagawa S. Effects of phosphatidylethanolamine N-methyltransferase on phospholipid composition, microvillus formation and bile salt resistance in LLC-PK1 cells. FEBS J. 2011;278:4768–81. https://doi.org/10.1111/j.1742-4658.2011.08377.x.
Morita S-Y, Ikeda Y, Tsuji T, Terada T. Molecular mechanisms for protection of hepatocytes against bile salt cytotoxicity. Chem Pharm Bull. 2019;67:333–40. https://doi.org/10.1248/cpb.c18-01029.
Moriwaki K, Chan FK-M. Necroptosis-independent signaling by the RIP kinases in inflammation. Cell Mol Life Sci. 2016;73:2325–34. https://doi.org/10.1007/s00018-016-2203-4.
Noé B, Schliess F, Wettstein M, Heinrich S, Häussinger D. Regulation of taurocholate excretion by a hypo-osmolarity-activated signal transduction pathway in rat liver. Gastroenterology. 1996;110:858–65. https://doi.org/10.1053/gast.1996.v110.pm8608896.
Norlin M, Wikvall K. Enzymes in the conversion of cholesterol into bile acids. Curr Mol Med. 2007;7:199–218. https://doi.org/10.2174/156652407780059168.
O’Brien KM, Allen KM, Rockwell CE, Towery K, Luyendyk JP, Copple BL. IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis. Am J Pathol. 2013;183:1498–507. https://doi.org/10.1016/j.ajpath.2013.07.019.
Oizumi K, Sekine S, Fukagai M, Susukida T, Ito K. Identification of bile acids responsible for inhibiting the bile salt export pump, leading to bile acid accumulation and cell toxicity in rat hepatocytes. J Pharm Sci. 2017;106:2412–9. https://doi.org/10.1016/j.xphs.2017.05.017.
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–8. https://doi.org/10.1126/science.284.5418.1365.
Pathak P, Liu H, Boehme S, Xie C, Krausz KW, Gonzalez F, Chiang JYL. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem. 2017;292:11055–69. https://doi.org/10.1074/jbc.M117.784322.
Pellicoro A, Faber KN. Review article: the function and regulation of proteins involved in bile salt biosynthesis and transport. Aliment Pharmacol Ther. 2007;26(Suppl 2):149–60. https://doi.org/10.1111/j.1365-2036.2007.03522.x.
Perez M-J, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15:1677–89. https://doi.org/10.3748/wjg.15.1677.
Perino A, Schoonjans K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci. 2015;36:847–57. https://doi.org/10.1016/j.tips.2015.08.002.
Pinkse GGM, Voorhoeve MP, Noteborn M, Terpstra OT, Bruijn JA, De Heer E. Hepatocyte survival depends on beta1-integrin-mediated attachment of hepatocytes to hepatic extracellular matrix. Liver Int. 2004;24:218–26. https://doi.org/10.1111/j.1478-3231.2004.0914.x.
Pusl T, Vennegeerts T, Wimmer R, Denk GU, Beuers U, Rust C. Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1. Biochem Biophys Res Commun. 2008;367:208–12. https://doi.org/10.1016/j.bbrc.2007.12.122.
Qiao L, McKinstry R, Gupta S, Gilfor D, Windle JJ, Hylemon PB, Grant S, Fisher PB, Dent P. Cyclin kinase inhibitor p21 potentiates bile acid-induced apoptosis in hepatocytes that is dependent on p53. Hepatology. 2002a;36:39–48. https://doi.org/10.1053/jhep.2002.33899.
Qiao L, Yacoub A, Studer E, Gupta S, Pei XY, Grant S, Hylemon PB, Dent P. Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes. Hepatology. 2002b;35:779–89. https://doi.org/10.1053/jhep.2002.32533.
Qiao L, Han SI, Fang Y, Park JS, Gupta S, Gilfor D, Amorino G, Valerie K, Sealy L, Engelhardt JF, Grant S, Hylemon PB, Dent P. Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol Cell Biol. 2003;23:3052–66. https://doi.org/10.1128/mcb.23.9.3052-3066.2003.
Rao Y-P, Studer EJ, Stravitz RT, Gupta S, Qiao L, Dent P, Hylemon PB. Activation of the Raf-1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes. Hepatology. 2002;35:307–14. https://doi.org/10.1053/jhep.2002.31104.
Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, Ullmer C, Knoefel WT, Herebian D, Mayatepek E, Häussinger D, Keitel V. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut. 2016;65:487–501. https://doi.org/10.1136/gutjnl-2015-309458.
Reich M, Klindt C, Deutschmann K, Spomer L, Häussinger D, Keitel V. Role of the G protein-coupled bile acid receptor TGR5 in liver damage. Dig Dis. 2017;35:235–40. https://doi.org/10.1159/000450917.
Reinehr R, Graf D, Häussinger D. Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation. Gastroenterology. 2003;125:839–53. https://doi.org/10.1016/s0016-5085(03)01055-2.
Reinehr R, Becker S, Wettstein M, Häussinger D. Involvement of the Src family kinase yes in bile salt-induced apoptosis. Gastroenterology. 2004;127:1540–57. https://doi.org/10.1053/j.gastro.2004.08.056.
Reinehr R, Becker S, Eberle A, Grether-Beck S, Häussinger D. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem. 2005a;280:27179–94. https://doi.org/10.1074/jbc.M414361200.
Reinehr R, Becker S, Keitel V, Eberle A, Grether-Beck S, Häussinger D. Bile salt-induced apoptosis involves NADPH oxidase isoform activation. Gastroenterology. 2005b;129:2009–31. https://doi.org/10.1053/j.gastro.2005.09.023.
Reinehr R, Sommerfeld A, Häussinger D. The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver. Biomol Concepts. 2013;4:129–42. https://doi.org/10.1515/bmc-2012-0047.
Rodrigues CM, Fan G, Wong PY, Kren BT, Steer CJ. Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med. 1998;4:165–78.
Rodrigues CM, Ma X, Linehan-Stieers C, Fan G, Kren BT, Steer CJ. Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation. Cell Death Differ. 1999;6:842–54. https://doi.org/10.1038/sj.cdd.4400560.
Rodrigues CMP, Solá S, Sharpe JC, Moura JJG, Steer CJ. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry. 2003;42:3070–80. https://doi.org/10.1021/bi026979d.
Roma MG, Milkiewicz P, Elias E, Coleman R. Control by signaling modulators of the sorting of canalicular transporters in rat hepatocyte couplets: role of the cytoskeleton. Hepatology. 2000;32:1342–56. https://doi.org/10.1053/jhep.2000.20519.
Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137–74. https://doi.org/10.1146/annurev.biochem.72.121801.161712.
Rust C, Karnitz LM, Paya CV, Moscat J, Simari RD, Gores GJ. The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem. 2000;275:20210–6. https://doi.org/10.1074/jbc.M909992199.
Rust C, Wild N, Bernt C, Vennegeerts T, Wimmer R, Beuers U. Bile acid-induced apoptosis in hepatocytes is caspase-6-dependent. J Biol Chem. 2009;284:2908–16. https://doi.org/10.1074/jbc.M804585200.
Sai Y, Nies AT, Arias IM. Bile acid secretion and direct targeting of mdr1-green fluorescent protein from Golgi to the canalicular membrane in polarized WIF-B cells. J Cell Sci. 1999;112(Pt 24):4535–45.
Salomone S, Waeber C. Selectivity and specificity of sphingosine-1-phosphate receptor ligands: caveats and critical thinking in characterizing receptor-mediated effects. Front Pharmacol. 2011;2:9. https://doi.org/10.3389/fphar.2011.00009.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17:1675–87. https://doi.org/10.1093/emboj/17.6.1675.
Schmitt M, Kubitz R, Lizun S, Wettstein M, Häussinger D. Regulation of the dynamic localization of the rat Bsep gene-encoded bile salt export pump by anisoosmolarity. Hepatology. 2001;33:509–18. https://doi.org/10.1053/jhep.2001.22648.
Schoemaker MH, Conde de la Rosa L, Buist-Homan M, Vrenken TE, Havinga R, Poelstra K, Haisma HJ, Jansen PLM, Moshage H. Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways. Hepatology. 2004;39:1563–73. https://doi.org/10.1002/hep.20246.
Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32. https://doi.org/10.1016/j.cell.2010.01.040.
Seyer P, Vallois D, Poitry-Yamate C, Schütz F, Metref S, Tarussio D, Maechler P, Staels B, Lanz B, Grueter R, Decaris J, Turner S, da Costa A, Preitner F, Minehira K, Foretz M, Thorens B. Hepatic glucose sensing is required to preserve β cell glucose competence. J Clin Invest. 2013;123:1662–76. https://doi.org/10.1172/JCI65538.
Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6. https://doi.org/10.1038/ncb0502-e131.
Sodeman T, Bronk SF, Roberts PJ, Miyoshi H, Gores GJ. Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas. Am J Physiol Gastrointest Liver Physiol. 2000;278:G992–9. https://doi.org/10.1152/ajpgi.2000.278.6.G992.
Sokol RJ, Winklhofer-Roob BM, Devereaux MW, McKim JM. Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids. Gastroenterology. 1995;109:1249–56. https://doi.org/10.1016/0016-5085(95)90585-5.
Sokol RJ, Dahl R, Devereaux MW, Yerushalmi B, Kobak GE, Gumpricht E. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J Pediatr Gastroenterol Nutr. 2005;41:235–43. https://doi.org/10.1097/01.mpg.0000170600.80640.88.
Sola S, Ma X, Castro RE, Kren BT, Steer CJ, Rodrigues CMP. Ursodeoxycholic acid modulates E2F-1 and p53 expression through a caspase-independent mechanism in transforming growth factor beta1-induced apoptosis of rat hepatocytes. J Biol Chem. 2003;278:48831–8. https://doi.org/10.1074/jbc.M300468200.
Solá S, Castro RE, Kren BT, Steer CJ, Rodrigues CMP. Modulation of nuclear steroid receptors by ursodeoxycholic acid inhibits TGF-beta1-induced E2F-1/p53-mediated apoptosis of rat hepatocytes. Biochemistry. 2004;43:8429–38. https://doi.org/10.1021/bi049781x.
Solá S, Amaral JD, Aranha MM, Steer CJ, Rodrigues CMP. Modulation of hepatocyte apoptosis: cross-talk between bile acids and nuclear steroid receptors. Curr Med Chem. 2006;13:3039–51. https://doi.org/10.2174/092986706778521823.
Solaas K, Ulvestad A, Söreide O, Kase BF. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts. J Lipid Res. 2000;41:1154–62.
Sommerfeld A, Reinehr R, Häussinger D. Tauroursodeoxycholate protects rat hepatocytes from bile acid-induced apoptosis via β1-integrin- and protein kinase A-dependent mechanisms. Cell Physiol Biochem. 2015;36:866–83. https://doi.org/10.1159/000430262.
Song K-H, Chiang JYL. Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis. Hepatology. 2006;43:117–25. https://doi.org/10.1002/hep.20919.
Soroka CJ, Boyer JL. Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations. Mol Aspects Med. 2014;37:3–14. https://doi.org/10.1016/j.mam.2013.05.001.
Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol. 2011:205–59. https://doi.org/10.1007/978-3-642-14541-4_5.
Takahashi S, Tanaka N, Golla S, Fukami T, Krausz KW, Polunas MA, Weig BC, Masuo Y, Xie C, Jiang C, Gonzalez FJ. Editor’s highlight: farnesoid X receptor protects against low-dose carbon tetrachloride-induced liver injury through the taurocholate-JNK pathway. Toxicol Sci. 2017;158:334–46. https://doi.org/10.1093/toxsci/kfx094.
Takikawa H, Beppu T, Seyama Y. Profiles of bile acids and their glucuronide and sulphate conjugates in the serum, urine and bile from patients undergoing bile drainage. Gut. 1985;26:38–42. https://doi.org/10.1136/gut.26.1.38.
Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun. 2000;273:251–60. https://doi.org/10.1006/bbrc.2000.2922.
Tamaki N, Hatano E, Taura K, Tada M, Kodama Y, Nitta T, Iwaisako K, Seo S, Nakajima A, Ikai I, Uemoto S. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol. 2008;294:G498–505. https://doi.org/10.1152/ajpgi.00482.2007.
Tan KP, Yang M, 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 Pharmacol. 2007;72:1380–90. https://doi.org/10.1124/mol.107.039370.
Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain K, Meier P. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell. 2011;43:432–48. https://doi.org/10.1016/j.molcel.2011.06.006.
Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7:678–93. https://doi.org/10.1038/nrd2619.
Trabelsi M-S, Lestavel S, Staels B, Collet X. Intestinal bile acid receptors are key regulators of glucose homeostasis. Proc Nutr Soc. 2017;76:192–202. https://doi.org/10.1017/S0029665116002834.
Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003;83:633–71. https://doi.org/10.1152/physrev.00027.2002.
Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis. 2010;28:220–4. https://doi.org/10.1159/000282091.
Treyer A, Müsch A. Hepatocyte polarity. Compr Physiol. 2013;3:243–87. https://doi.org/10.1002/cphy.c120009.
Tsuchiya S, Tsuji M, Morio Y, Oguchi K. Involvement of endoplasmic reticulum in glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes. Toxicol Lett. 2006;166:140–9. https://doi.org/10.1016/j.toxlet.2006.06.006.
Usechak P, Gates A, Webster CR. Activation of focal adhesion kinase and JNK contributes to the extracellular matrix and cAMP-GEF mediated survival from bile acid induced apoptosis in rat hepatocytes. J Hepatol. 2008;49:251–61. https://doi.org/10.1016/j.jhep.2008.04.015.
Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15:135–47. https://doi.org/10.1038/nrm3737.
Vucur M, Reisinger F, Gautheron J, Janssen J, Roderburg C, Cardenas DV, Kreggenwinkel K, Koppe C, Hammerich L, Hakem R, Unger K, Weber A, Gassler N, Luedde M, Frey N, Neumann UP, Tacke F, Trautwein C, Heikenwalder M, Luedde T. RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation. Cell Rep. 2013;4:776–90. https://doi.org/10.1016/j.celrep.2013.07.035.
Wakabayashi Y, Dutt P, Lippincott-Schwartz J, Arias IM. Rab11a and myosin Vb are required for bile canalicular formation in WIF-B9 cells. Proc Natl Acad Sci U S A. 2005;102:15087–92. https://doi.org/10.1073/pnas.0503702102.
Walczak H. TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev. 2011;244:9–28. https://doi.org/10.1111/j.1600-065X.2011.01066.x.
Wang H, Sun L, Su L, Rizo J, Liu L, Wang L-F, Wang F-S, Wang X. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014;54:133–46. https://doi.org/10.1016/j.molcel.2014.03.003.
Wang Y, Aoki H, Yang J, Peng K, Liu R, Li X, Qiang X, Sun L, Gurley EC, Lai G, Zhang L, Liang G, Nagahashi M, Takabe K, Pandak WM, Hylemon PB, Zhou H. The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology. 2017;65:2005–18. https://doi.org/10.1002/hep.29076.
Wang J, Dong R, Zheng S. Roles of the inflammasome in the gut-liver axis (review). Mol Med Rep. 2019;19:3–14. https://doi.org/10.3892/mmr.2018.9679.
Webster CRL, Anwer MS. Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells. Am J Physiol Gastrointest Liver Physiol. 2016;310:G865–73. https://doi.org/10.1152/ajpgi.00253.2015.
Webster CRL, Usechak P, Anwer MS. cAMP inhibits bile acid-induced apoptosis by blocking caspase activation and cytochrome c release. Am J Physiol Gastrointest Liver Physiol. 2002;283:G727–38. https://doi.org/10.1152/ajpgi.00410.2001.
Webster CRL, Johnston AN, Anwer MS. Protein kinase Cδ protects against bile acid apoptosis by suppressing proapoptotic JNK and BIM pathways in human and rat hepatocytes. Am J Physiol Gastrointest Liver Physiol. 2014;307:G1207–15. https://doi.org/10.1152/ajpgi.00165.2014.
Wei J, Qiu DK, Ma X. Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver disease. J Dig Dis. 2009;10:85–90. https://doi.org/10.1111/j.1751-2980.2009.00369.x.
Werneburg NW, Yoon J-H, Higuchi H, Gores GJ. Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol Gastrointest Liver Physiol. 2003;285:G31–6. https://doi.org/10.1152/ajpgi.00536.2002.
Woods A, Heslegrave AJ, Muckett PJ, Levene AP, Clements M, Mobberley M, Ryder TA, Abu-Hayyeh S, Williamson C, Goldin RD, Ashworth A, Withers DJ, Carling D. LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice. Biochem J. 2011;434:49–60. https://doi.org/10.1042/BJ20101721.
Xia X, Francis H, Glaser S, Alpini G, LeSage G. Bile acid interactions with cholangiocytes. World J Gastroenterol. 2006;12:3553–63. https://doi.org/10.3748/wjg.v12.i22.3553.
Yang JI, Yoon J-H, Myung SJ, Gwak G-Y, Kim W, Chung GE, Lee SH, Lee S-M, Kim CY, Lee H-S. Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes. Biochem Biophys Res Commun. 2007;361:156–61. https://doi.org/10.1016/j.bbrc.2007.07.001.
Yerushalmi B, Dahl R, Devereaux MW, Gumpricht E, Sokol RJ. Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology. 2001;33:616–26. https://doi.org/10.1053/jhep.2001.22702.
Yin XM. Bid, a critical mediator for apoptosis induced by the activation of Fas/TNF-R1 death receptors in hepatocytes. J Mol Med. 2000;78:203–11. https://doi.org/10.1007/s001090000099.
Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science. 2000;290:1761–5. https://doi.org/10.1126/science.290.5497.1761.
Zhang G, Park MA, Mitchell C, Walker T, Hamed H, Studer E, Graf M, Rahmani M, Gupta S, Hylemon PB, Fisher PB, Grant S, Dent P. Multiple cyclin kinase inhibitors promote bile acid-induced apoptosis and autophagy in primary hepatocytes via p53-CD95-dependent signaling. J Biol Chem. 2008;283:24343–58. https://doi.org/10.1074/jbc.M803444200.
Zhang W, Chen L, Feng H, Wang W, Cai Y, Qi F, Tao X, Liu J, Shen Y, Ren X, Chen X, Xu J, Shen Y. Rifampicin-induced injury in HepG2 cells is alleviated by TUDCA via increasing bile acid transporters expression and enhancing the Nrf2-mediated adaptive response. Free Radic Biol Med. 2017;112:24–35. https://doi.org/10.1016/j.freeradbiomed.2017.07.003.
Zhou W, Yuan J. Necroptosis in health and diseases. Semin Cell Dev Biol. 2014;35:14–23. https://doi.org/10.1016/j.semcdb.2014.07.013.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Engin, A. (2021). Bile Acid Toxicity and Protein Kinases. In: Engin, A.B., Engin, A. (eds) Protein Kinase-mediated Decisions Between Life and Death. Advances in Experimental Medicine and Biology, vol 1275. Springer, Cham. https://doi.org/10.1007/978-3-030-49844-3_9
Download citation
DOI: https://doi.org/10.1007/978-3-030-49844-3_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-49843-6
Online ISBN: 978-3-030-49844-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)