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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張美惠(Mei Hwei Chang) | |
dc.contributor.author | Shang-Hsin Wu | en |
dc.contributor.author | 吳上欣 | zh_TW |
dc.date.accessioned | 2021-07-09T15:53:12Z | - |
dc.date.available | 2022-03-13 | |
dc.date.copyright | 2020-03-13 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-11-26 | |
dc.identifier.citation | Adachi, Y., H. Kobayashi, Y. Kurumi, M. Shouji, M. Kitano and T. Yamamoto (1991). 'ATP-dependent taurocholate transport by rat liver canalicular membrane vesicles.' Hepatology 14(4 Pt 1): 655-659.
Aida, K., H. Hayashi, K. Inamura, T. Mizuno and Y. Sugiyama (2014). 'Differential roles of ubiquitination in the degradation mechanism of cell surface-resident bile salt export pump and multidrug resistance-associated protein 2.' Mol Pharmacol 85(3): 482-491. Allaire, M., P. E. Rautou, P. Codogno and S. Lotersztajn (2019). 'Autophagy in liver diseases: Time for translation?' J Hepatol 70(5): 985-998. Alnouti, Y. (2009). 'Bile Acid sulfation: a pathway of bile acid elimination and detoxification.' Toxicol Sci 108(2): 225-246. Andra, K., H. Lassmann, R. Bittner, S. Shorny, R. Fassler, F. Propst and G. Wiche (1997). 'Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture.' Genes Dev 11(23): 3143-3156. Ballatori, N., W. V. Christian, S. G. Wheeler and C. L. Hammond (2013). 'The heteromeric organic solute transporter, OSTalpha-OSTbeta/SLC51: a transporter for steroid-derived molecules.' Mol Aspects Med 34(2-3): 683-692. Ballatori, N., J. F. Rebbeor, G. C. Connolly, D. J. Seward, B. E. Lenth, J. H. Henson, P. Sundaram and J. L. Boyer (2000). 'Bile salt excretion in skate liver is mediated by a functional analog of Bsep/Spgp, the bile salt export pump.' Am J Physiol Gastrointest Liver Physiol 278(1): G57-63. Beck, R., M. Rawet, F. T. Wieland and D. Cassel (2009). 'The COPI system: molecular mechanisms and function.' FEBS Lett 583(17): 2701-2709. Berger, K. and M. J. Moeller (2011). 'Cofilin-1 in the podocyte: a molecular switch for actin dynamics.' Int Urol Nephrol 43(1): 273-275. Bettayeb, K., B. V. Hooli, A. R. Parrado, L. Randolph, D. Varotsis, S. Aryal, J. Gresack, R. E. Tanzi, P. Greengard and M. Flajolet (2016). 'Relevance of the COPI complex for Alzheimer's disease progression in vivo.' Proc Natl Acad Sci U S A 113(19): 5418-5423. Bezerra, J. A., R. G. Wells, C. L. Mack, S. J. Karpen, J. H. Hoofnagle, E. Doo and R. J. Sokol (2018). 'BILIARY ATRESIA: Clinical and Research Challenges for the 21(st) Century.' Hepatology 68(3): 1163-1173. Bohme, M., M. Muller, I. Leier, G. Jedlitschky and D. Keppler (1994). 'Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver.' Gastroenterology 107(1): 255-265. Bolder, U., H. T. Ton-Nu, C. D. Schteingart, E. Frick and A. F. Hofmann (1997). 'Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion.' Gastroenterology 112(1): 214-225. Bonifacino, J. S. (2014). 'Adaptor proteins involved in polarized sorting.' J Cell Biol 204(1): 7-17. Bossard, R., B. Stieger, B. O'Neill, G. Fricker and P. J. Meier (1993). 'Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver.' J Clin Invest 91(6): 2714-2720. Bouameur, J. E., B. Favre, L. Fontao, P. Lingasamy, N. Begre and L. Borradori (2014). 'Interaction of plectin with keratins 5 and 14: dependence on several plectin domains and keratin quaternary structure.' J Invest Dermatol 134(11): 2776-2783. Bremmelgaard, A. and J. Sjovall (1980). 'Hydroxylation of cholic, chenodeoxycholic, and deoxycholic acids in patients with intrahepatic cholestasis.' J Lipid Res 21(8): 1072-1081. Bull, L. N. and R. J. Thompson (2018). 'Progressive Familial Intrahepatic Cholestasis.' Clin Liver Dis 22(4): 657-669. Bull, L. N., M. J. van Eijk, L. Pawlikowska, J. A. DeYoung, J. A. Juijn, M. Liao, L. W. Klomp, N. Lomri, R. Berger, B. F. Scharschmidt, A. S. Knisely, R. H. Houwen and N. B. Freimer (1998). 'A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.' Nat Genet 18(3): 219-224. Byrne, J. A., S. S. Strautnieks, G. Ihrke, F. Pagani, A. S. Knisely, K. J. Linton, G. Mieli-Vergani and R. J. Thompson (2009). 'Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing.' Hepatology 49(2): 553-567. Byrne, J. A., S. S. Strautnieks, G. Mieli-Vergani, C. F. Higgins, K. J. Linton and R. J. Thompson (2002). 'The human bile salt export pump: characterization of substrate specificity and identification of inhibitors.' Gastroenterology 123(5): 1649-1658. Cai, S. Y., L. Wang, N. Ballatori and J. L. Boyer (2001). 'Bile salt export pump is highly conserved during vertebrate evolution and its expression is inhibited by PFIC type II mutations.' Am J Physiol Gastrointest Liver Physiol 281(2): G316-322. Caillat, C., S. Maity, N. Miguet, W. H. Roos and W. Weissenhorn (2019). 'The role of VPS4 in ESCRT-III polymer remodeling.' Biochem Soc Trans 47(1): 441-448. Chan, J. and J. L. Vandeberg (2012). 'Hepatobiliary transport in health and disease.' Clin Lipidol 7(2): 189-202. Chan, W., G. Calderon, A. L. Swift, J. Moseley, S. Li, H. Hosoya, I. M. Arias and D. F. Ortiz (2005). 'Myosin II regulatory light chain is required for trafficking of bile salt export protein to the apical membrane in Madin-Darby canine kidney cells.' J Biol Chem 280(25): 23741-23747. Chen, H. L., P. S. Chang, H. C. Hsu, Y. H. Ni, H. Y. Hsu, J. H. Lee, Y. M. Jeng, W. Y. Shau and M. H. Chang (2002). 'FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels.' J Pediatr 140(1): 119-124. Chen, H. L., H. L. Chen, Y. J. Liu, C. H. Feng, C. Y. Wu, M. K. Shyu, R. H. Yuan and M. H. Chang (2005). 'Developmental expression of canalicular transporter genes in human liver.' J Hepatol 43(3): 472-477. Chen, H. L., H. Y. Li, J. F. Wu, S. H. Wu, H. L. Chen, Y. H. Yang, Y. H. Hsu, B. Y. Liou, M. H. Chang and Y. H. Ni (2019). 'Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges.' J Pediatr 205: 153-159 e156. Chen, H. L., Y. J. Liu, Y. N. Su, N. Y. Wang, S. H. Wu, Y. H. Ni, H. Y. Hsu, T. C. Wu and M. H. Chang (2008). 'Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography.' J Pediatr 153(6): 825-832. Chen, H. L., S. H. Wu, S. H. Hsu, B. Y. Liou, H. L. Chen and M. H. Chang (2018). 'Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases.' J Biomed Sci 25(1): 75. Chen, Y., N. Guldiken, M. Spurny, H. H. Mohammed, J. Haybaeck, M. J. Pollheimer, P. Fickert, N. Gassler, M. K. Jeon, C. Trautwein and P. Strnad (2015). 'Loss of keratin 19 favours the development of cholestatic liver disease through decreased ductular reaction.' J Pathol 237(3): 343-354. Cheng, C. C., Y. C. Lai, Y. S. Lai, Y. H. Hsu, W. T. Chao, K. C. Sia, Y. H. Tseng and Y. H. Liu (2015). 'Transient knockdown-mediated deficiency in plectin alters hepatocellular motility in association with activated FAK and Rac1-GTPase.' Cancer Cell Int 15: 29. Cheng, X., D. Buckley and C. D. Klaassen (2007). 'Regulation of hepatic bile acid transporters Ntcp and Bsep expression.' Biochem Pharmacol 74(11): 1665-1676. Cheng, Y., S. Chen, C. Freeden, W. Chen, Y. Zhang, P. Abraham, D. M. Nelson, W. G. Humphreys, J. Gan and Y. Lai (2017). 'Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.' J Pharmacol Exp Ther 362(3): 385-394. Cheng, Y., C. Freeden, Y. Zhang, P. Abraham, H. Shen, D. Wescott, W. G. Humphreys, J. Gan and Y. Lai (2016). 'Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment.' Biopharm Drug Dispos 37(5): 276-286. Chiang, J. Y. (2002). 'Bile acid regulation of gene expression: roles of nuclear hormone receptors.' Endocr Rev 23(4): 443-463. Chiang, J. Y. L. and J. M. Ferrell (2019). 'Bile Acids as Metabolic Regulators and Nutrient Sensors.' Annu Rev Nutr 39: 175-200. Childs, S., R. L. Yeh, E. Georges and V. Ling (1995). 'Identification of a sister gene to P-glycoprotein.' Cancer Res 55(10): 2029-2034. Childs, S., R. L. Yeh, D. Hui and V. Ling (1998). 'Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein.' Cancer Res 58(18): 4160-4167. Christ, L., C. Raiborg, E. M. Wenzel, C. Campsteijn and H. Stenmark (2017). 'Cellular Functions and Molecular Mechanisms of the ESCRT Membrane-Scission Machinery.' Trends Biochem Sci 42(1): 42-56. Claro da Silva, T., J. E. Polli and P. W. Swaan (2013). 'The solute carrier family 10 (SLC10): beyond bile acid transport.' Mol Aspects Med 34(2-3): 252-269. Conti, M. A. and R. S. Adelstein (2008). 'Nonmuscle myosin II moves in new directions.' J Cell Sci 121(Pt 1): 11-18. Cresawn, K. O., B. A. Potter, A. Oztan, C. J. Guerriero, G. Ihrke, J. R. Goldenring, G. Apodaca and O. A. Weisz (2007). 'Differential involvement of endocytic compartments in the biosynthetic traffic of apical proteins.' Embo j 26(16): 3737-3748. Crocenzi, F. A., A. E. Zucchetti, A. C. Boaglio, I. R. Barosso, E. J. Sanchez Pozzi, A. D. Mottino and M. G. Roma (2012). 'Localization status of hepatocellular transporters in cholestasis.' Front Biosci (Landmark Ed) 17: 1201-1218. Curwin, A. J., J. von Blume and V. Malhotra (2012). 'Cofilin-mediated sorting and export of specific cargo from the Golgi apparatus in yeast.' Mol Biol Cell 23(12): 2327-2338. Daday, C., K. Kolsek and F. Grater (2017). 'The mechano-sensing role of the unique SH3 insertion in plakin domains revealed by Molecular Dynamics simulations.' Sci Rep 7(1): 11669. Dawson, P. A., M. L. Hubbert and A. Rao (2010). 'Getting the mOST from OST: Role of organic solute transporter, OSTalpha-OSTbeta, in bile acid and steroid metabolism.' Biochim Biophys Acta 1801(9): 994-1004. de Vree, J. M., E. Jacquemin, E. Sturm, D. Cresteil, P. J. Bosma, J. Aten, J. F. Deleuze, M. Desrochers, M. Burdelski, O. Bernard, R. P. Oude Elferink and M. Hadchouel (1998). 'Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.' Proc Natl Acad Sci U S A 95(1): 282-287. Decaens, C., M. Durand, B. Grosse and D. Cassio (2008). 'Which in vitro models could be best used to study hepatocyte polarity?' Biol Cell 100(7): 387-398. Delacour, D. and R. Jacob (2006). 'Apical protein transport.' Cell Mol Life Sci 63(21): 2491-2505. Deutschmann, K., M. Reich, C. Klindt, C. Droge, L. Spomer, D. Haussinger and V. Keitel (2018). 'Bile acid receptors in the biliary tree: TGR5 in physiology and disease.' Biochim Biophys Acta Mol Basis Dis 1864(4 Pt B): 1319-1325. Donaldson, J. G., D. L. Johnson and D. Dutta (2016). 'Rab and Arf G proteins in endosomal trafficking and cell surface homeostasis.' Small GTPases 7(4): 247-251. Droge, C., M. Bonus, U. Baumann, C. Klindt, E. Lainka, S. Kathemann, F. Brinkert, E. Grabhorn, E. D. Pfister, D. Wenning, A. Fichtner, D. N. Gotthardt, K. H. Weiss, P. McKiernan, R. D. Puri, I. C. Verma, S. Kluge, H. Gohlke, L. Schmitt, R. Kubitz, D. Haussinger and V. Keitel (2017). 'Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.' J Hepatol 67(6): 1253-1264. Elliott, C. E., B. Becker, S. Oehler, M. J. Castanon, R. Hauptmann and G. Wiche (1997). 'Plectin transcript diversity: identification and tissue distribution of variants with distinct first coding exons and rodless isoforms.' Genomics 42(1): 115-125. Ellis, J. L., K. E. Bove, E. G. Schuetz, D. Leino, C. A. Valencia, J. D. Schuetz, A. Miethke and C. Yin (2018). 'Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency.' Hepatology 67(4): 1531-1545. Erpapazoglou, Z., M. Dhaoui, M. Pantazopoulou, F. Giordano, M. Mari, S. Leon, G. Raposo, F. Reggiori and R. Haguenauer-Tsapis (2012). 'A dual role for K63-linked ubiquitin chains in multivesicular body biogenesis and cargo sorting.' Mol Biol Cell 23(11): 2170-2183. Esteller, A. (2008). 'Physiology of bile secretion.' World J Gastroenterol 14(37): 5641-5649. Fickert, P., A. Fuchsbichler, M. Wagner, D. Silbert, K. Zatloukal, H. Denk and M. Trauner (2009). 'The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice.' Hepatology 50(3): 893-899. Fickert, P. and M. Wagner (2017). 'Biliary bile acids in hepatobiliary injury - What is the link?' J Hepatol 67(3): 619-631. Folsch, H., P. E. Mattila and O. A. Weisz (2009). 'Taking the scenic route: biosynthetic traffic to the plasma membrane in polarized epithelial cells.' Traffic 10(8): 972-981. Fu, D., J. Lippincott-Schwartz and I. M. Arias (2011). 'Cellular mechanism of bile acid-accelerated hepatocyte polarity.' Small GTPases 2(6): 314-317. Fuchs, C. D., G. Paumgartner, A. Wahlstrom, P. Schwabl, T. Reiberger, N. Leditznig, T. Stojakovic, N. Rohr-Udilova, P. Chiba, H. U. Marschall and M. Trauner (2017). 'Metabolic preconditioning protects BSEP/ABCB11(-/-) mice against cholestatic liver injury.' J Hepatol 66(1): 95-101. Fuchs, P., D. Spazierer and G. Wiche (2005). 'Plectin rodless isoform expression and its detection in mouse brain.' Cell Mol Neurobiol 25(7): 1141-1150. Fujiwara, R., M. Haag, E. Schaeffeler, A. T. Nies, U. M. Zanger and M. Schwab (2018). 'Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia.' Hepatology 67(4): 1609-1619. Gao, B., M. V. St Pierre, B. Stieger and P. J. Meier (2004). 'Differential expression of bile salt and organic anion transporters in developing rat liver.' J Hepatol 41(2): 201-208. Ge, L., S. Baskaran, R. Schekman and J. H. Hurley (2014). 'The protein-vesicle network of autophagy.' Curr Opin Cell Biol 29: 18-24. Gerloff, T., B. Stieger, B. Hagenbuch, J. Madon, L. Landmann, J. Roth, A. F. Hofmann and P. J. Meier (1998). 'The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.' J Biol Chem 273(16): 10046-10050. Girard, M., F. Lacaille, V. Verkarre, R. Mategot, G. Feldmann, A. Grodet, F. Sauvat, S. Irtan, A. Davit-Spraul, E. Jacquemin, F. Ruemmele, D. Rainteau, O. Goulet, V. Colomb, C. Chardot, A. Henrion-Caude and D. Debray (2014). 'MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease.' Hepatology 60(1): 301-310. Gissen, P. and I. M. Arias (2015). 'Structural and functional hepatocyte polarity and liver disease.' J Hepatol 63(4): 1023-1037. Gissen, P., L. Tee, C. A. Johnson, E. Genin, A. Caliebe, D. Chitayat, C. Clericuzio, J. Denecke, M. Di Rocco, B. Fischler, D. FitzPatrick, A. Garcia-Cazorla, D. Guyot, S. Jacquemont, S. Koletzko, B. Leheup, H. Mandel, M. T. Sanseverino, R. H. Houwen, P. J. McKiernan, D. A. Kelly and E. R. Maher (2006). 'Clinical and molecular genetic features of ARC syndrome.' Hum Genet 120(3): 396-409. Glozman, R., T. Okiyoneda, C. M. Mulvihill, J. M. Rini, H. Barriere and G. L. Lukacs (2009). 'N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic.' J Cell Biol 184(6): 847-862. Golachowska, M. R., D. Hoekstra and I. S. C. van (2010). 'Recycling endosomes in apical plasma membrane domain formation and epithelial cell polarity.' Trends Cell Biol 20(10): 618-626. Goldmann, W. H. (2018). 'Intermediate filaments and cellular mechanics.' Cell Biol Int 42(2): 132-138. Gomez-Ospina, N., C. J. Potter, R. Xiao, K. Manickam, M. S. Kim, K. H. Kim, B. L. Shneider, J. L. Picarsic, T. A. Jacobson, J. Zhang, W. He, P. Liu, A. S. Knisely, M. J. Finegold, D. M. Muzny, E. Boerwinkle, J. R. Lupski, S. E. Plon, R. A. Gibbs, C. M. Eng, Y. Yang, G. C. Washington, M. H. Porteus, W. E. Berquist, N. Kambham, R. J. Singh, F. Xia, G. M. Enns and D. D. Moore (2016). 'Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.' Nat Commun 7: 10713. Gonzales, E., S. A. Taylor, A. Davit-Spraul, A. Thebaut, N. Thomassin, C. Guettier, P. F. Whitington and E. Jacquemin (2017). 'MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease.' Hepatology 65(1): 164-173. Gonzales, P. A., T. Pisitkun, J. D. Hoffert, D. Tchapyjnikov, R. A. Star, R. Kleta, N. S. Wang and M. A. Knepper (2009). 'Large-scale proteomics and phosphoproteomics of urinary exosomes.' J Am Soc Nephrol 20(2): 363-379. Goto, K., K. Sugiyama, T. Sugiura, T. Ando, F. Mizutani, K. Terabe, K. Ban and H. Togari (2003). 'Bile salt export pump gene mutations in two Japanese patients with progressive familial intrahepatic cholestasis.' J Pediatr Gastroenterol Nutr 36(5): 647-650. Green, R. M., F. Hoda and K. L. Ward (2000). 'Molecular cloning and characterization of the murine bile salt export pump.' Gene 241(1): 117-123. Greenblatt, M. B., K. H. Park, H. Oh, J. M. Kim, D. Y. Shin, J. M. Lee, J. W. Lee, A. Singh, K. Y. Lee, D. Hu, C. Xiao, J. F. Charles, J. M. Penninger, S. Lotinun, R. Baron, S. Ghosh and J. H. Shim (2015). 'CHMP5 controls bone turnover rates by dampening NF-kappaB activity in osteoclasts.' J Exp Med 212(8): 1283-1301. Groen, A., M. R. Romero, C. Kunne, S. J. Hoosdally, P. H. Dixon, C. Wooding, C. Williamson, J. Seppen, K. Van den Oever, K. S. Mok, C. C. Paulusma, K. J. Linton and R. P. Oude Elferink (2011). 'Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity.' Gastroenterology 141(5): 1927-1937 e1921-1924. Grumati, P. and I. Dikic (2018). 'Ubiquitin signaling and autophagy.' J Biol Chem 293(15): 5404-5413. Haag, C., T. Pohlmann and M. Feldbrugge (2017). 'The ESCRT regulator Did2 maintains the balance between long-distance endosomal transport and endocytic trafficking.' PLoS Genet 13(4): e1006734. Hayashi, H., K. Inamura, K. Aida, S. Naoi, R. Horikawa, H. Nagasaka, T. Takatani, T. Fukushima, A. Hattori, T. Yabuki, I. Horii and Y. Sugiyama (2012). 'AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function.' Hepatology 55(6): 1889-1900. Hayashi, H., T. Mizuno, R. Horikawa, H. Nagasaka, T. Yabuki, H. Takikawa and Y. Sugiyama (2012). '4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration.' J Hepatol 56(5): 1136-1144. Hayashi, H. and Y. Sugiyama (2007). '4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps.' Hepatology 45(6): 1506-1516. Hayashi, H. and Y. Sugiyama (2009). 'Short-chain ubiquitination is associated with the degradation rate of a cell-surface-resident bile salt export pump (BSEP/ABCB11).' Mol Pharmacol 75(1): 143-150. Hayashi, H., T. Takada, H. Suzuki, H. Akita and Y. Sugiyama (2005). 'Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11.' Hepatology 41(4): 916-924. Hayashi, H., T. Takada, H. Suzuki, R. Onuki, A. F. Hofmann and Y. Sugiyama (2005). 'Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate: a comparison of human BSEP with rat Bsep.' Biochim Biophys Acta 1738(1-3): 54-62. Henkel, A. S., B. LeCuyer, S. Olivares and R. M. Green (2017). 'Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice.' Cell Mol Gastroenterol Hepatol 3(2): 261-271. Hiebl, V., A. Ladurner, S. Latkolik and V. M. Dirsch (2018). 'Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR.' Biotechnol Adv 36(6): 1657-1698. Hofmann, A. F. (1999). 'The continuing importance of bile acids in liver and intestinal disease.' Arch Intern Med 159(22): 2647-2658. Hofmann, A. F., L. R. Hagey and M. D. Krasowski (2010). 'Bile salts of vertebrates: structural variation and possible evolutionary significance.' J Lipid Res 51(2): 226-246. Hohmann, T. and F. Dehghani (2019). 'The Cytoskeleton-A Complex Interacting Meshwork.' Cells 8(4). Homolya, L., D. Fu, P. Sengupta, M. Jarnik, J. P. Gillet, L. Vitale-Cross, J. S. Gutkind, J. Lippincott-Schwartz and I. M. Arias (2014). 'LKB1/AMPK and PKA control ABCB11 trafficking and polarization in hepatocytes.' PLoS One 9(3): e91921. Horgan, C. P., S. R. Hanscom, E. E. Kelly and M. W. McCaffrey (2012). 'Tumor susceptibility gene 101 (TSG101) is a novel binding-partner for the class II Rab11-FIPs.' PLoS One 7(2): e32030. Hu, L., Z. Huang, Z. Wu, A. Ali and A. Qian (2018). 'Mammalian Plakins, Giant Cytolinkers: Versatile Biological Functions and Roles in Cancer.' Int J Mol Sci 19(4). Hunt, C. M., J. I. Papay, V. Stanulovic and A. Regev (2017). 'Drug rechallenge following drug-induced liver injury.' Hepatology 66(2): 646-654. Hurley, J. H. and B. A. Schulman (2014). 'Atomistic autophagy: the structures of cellular self-digestion.' Cell 157(2): 300-311. Ihrke, G., E. B. Neufeld, T. Meads, M. R. Shanks, D. Cassio, M. Laurent, T. A. Schroer, R. E. Pagano and A. L. Hubbard (1993). 'WIF-B cells: an in vitro model for studies of hepatocyte polarity.' J Cell Biol 123(6 Pt 2): 1761-1775. Ikegami, T. and A. Honda (2018). 'Reciprocal interactions between bile acids and gut microbiota in human liver diseases.' Hepatol Res 48(1): 15-27. Jacob, J. T., P. A. Coulombe, R. Kwan and M. B. Omary (2018). 'Types I and II Keratin Intermediate Filaments.' Cold Spring Harb Perspect Biol 10(4). Jansen, P. L., S. S. Strautnieks, E. Jacquemin, M. Hadchouel, E. M. Sokal, G. J. Hooiveld, J. H. Koning, A. De Jager-Krikken, F. Kuipers, F. Stellaard, C. M. Bijleveld, A. Gouw, H. Van Goor, R. J. Thompson and M. Muller (1999). 'Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.' Gastroenterology 117(6): 1370-1379. Jirouskova, M., K. Nepomucka, G. Oyman-Eyrilmez, A. Kalendova, H. Havelkova, L. Sarnova, K. Chalupsky, B. Schuster, O. Benada, P. Miksatkova, M. Kuchar, O. Fabian, R. Sedlacek, G. Wiche and M. Gregor (2018). 'Plectin controls biliary tree architecture and stability in cholestasis.' J Hepatol 68(5): 1006-1017. Jurica, J., G. Dovrtelova, K. Noskova and O. Zendulka (2016). 'Bile acids, nuclear receptors and cytochrome P450.' Physiol Res 65(Supplementum 4): S427-S440. Keitel, V., M. Burdelski, U. Warskulat, T. Kuhlkamp, D. Keppler, D. Haussinger and R. Kubitz (2005). 'Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.' Hepatology 41(5): 1160-1172. Keppler, D. (2014). 'The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia.' Drug Metab Dispos 42(4): 561-565. Ketema, M., P. Secades, M. Kreft, L. Nahidiazar, H. Janssen, K. Jalink, J. M. de Pereda and A. Sonnenberg (2015). 'The rod domain is not essential for the function of plectin in maintaining tissue integrity.' Mol Biol Cell 26(13): 2402-2417. Kim, S. R., Y. Saito, M. Itoda, K. Maekawa, M. Kawamoto, N. Kamatani, S. Ozawa and J. Sawada (2009). 'Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population.' Drug Metab Pharmacokinet 24(3): 277-281. Kipp, H. and I. M. Arias (2000). 'Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters.' Semin Liver Dis 20(3): 339-351. Kipp, H. and I. M. Arias (2000). 'Newly synthesized canalicular ABC transporters are directly targeted from the Golgi to the hepatocyte apical domain in rat liver.' J Biol Chem 275(21): 15917-15925. Kipp, H. and I. M. Arias (2002). 'Trafficking of canalicular ABC transporters in hepatocytes.' Annu Rev Physiol 64: 595-608. Kipp, H., N. Pichetshote and I. M. Arias (2001). 'Transporters on demand: intrahepatic pools of canalicular ATP binding cassette transporters in rat liver.' J Biol Chem 276(10): 7218-7224. Komander, D. (2009). 'The emerging complexity of protein ubiquitination.' Biochem Soc Trans 37(Pt 5): 937-953. Kong, J., B. B. Liu, S. D. Wu, Y. Wang, Q. Q. Jiang and E. L. Guo (2014). 'Enhancement of interaction of BSEP and HAX-1 on the canalicular membrane of hepatocytes in a mouse model of cholesterol cholelithiasis.' Int J Clin Exp Pathol 7(4): 1644-1650. Kubitz, R., C. Droge, J. Stindt, K. Weissenberger and D. Haussinger (2012). 'The bile salt export pump (BSEP) in health and disease.' Clin Res Hepatol Gastroenterol 36(6): 536-553. Kubitz, R., N. Saha, T. Kuhlkamp, S. Dutta, S. vom Dahl, M. Wettstein and D. Haussinger (2004). 'Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver.' J Biol Chem 279(11): 10323-10330. Kullak-Ublick, G. A., B. Stieger, B. Hagenbuch and P. J. Meier (2000). 'Hepatic transport of bile salts.' Semin Liver Dis 20(3): 273-292. Kumar, H., K. Pushpa, A. Kumari, K. Verma, R. Pergu and S. V. S. Mylavarapu (2019). 'The exocyst complex and Rab5 are required for abscission by localizing ESCRT III subunits to the cytokinetic bridge.' J Cell Sci 132(14): jcs226001. Kuroki, S., K. Shimazu, M. Kuwabara, M. Une, K. Kihira, T. Kuramoto and T. Hoshita (1985). 'Identification of bile alcohols in human bile.' J Lipid Res 26(2): 230-240. Lam, P., C. L. Pearson, C. J. Soroka, S. Xu, A. Mennone and J. L. Boyer (2007). '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 293(5): C1709-1716. Lam, P., C. J. Soroka and J. L. Boyer (2010). 'The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease.' Semin Liver Dis 30(2): 125-133. Lam, P., R. Wang and V. Ling (2005). 'Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice.' Biochemistry 44(37): 12598-12605. Lam, P., S. Xu, C. J. Soroka and J. L. Boyer (2012). 'A C-terminal tyrosine-based motif in the bile salt export pump directs clathrin-dependent endocytosis.' Hepatology 55(6): 1901-1911. Lauwers, E., C. Jacob and B. Andre (2009). 'K63-linked ubiquitin chains as a specific signal for protein sorting into the multivesicular body pathway.' J Cell Biol 185(3): 493-502. Lecureur, V., D. Sun, P. Hargrove, E. G. Schuetz, R. B. Kim, L. B. Lan and J. D. Schuetz (2000). 'Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.' Mol Pharmacol 57(1): 24-35. Lee, C. S., A. Kimura, J. F. Wu, Y. H. Ni, H. Y. Hsu, M. H. Chang, H. Nittono and H. L. Chen (2017). 'Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis.' J Lipid Res 58(3): 607-614. Li, C. C., T. C. Chiang, T. S. Wu, G. Pacheco-Rodriguez, J. Moss and F. J. Lee (2007). 'ARL4D recruits cytohesin-2/ARNO to modulate actin remodeling.' Mol Biol Cell 18(11): 4420-4437. Lim, K. L., K. C. Chew, J. M. Tan, C. Wang, K. K. Chung, Y. Zhang, Y. Tanaka, W. Smith, S. Engelender, C. A. Ross, V. L. Dawson and T. M. Dawson (2005). 'Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation.' J Neurosci 25(8): 2002-2009. Linton, K. J. (2015). 'Lipid flopping in the liver.' Biochem Soc Trans 43(5): 1003-1010. Liu, C. G., C. Maercker, M. J. Castanon, R. Hauptmann and G. Wiche (1996). 'Human plectin: organization of the gene, sequence analysis, and chromosome localization (8q24).' Proc Natl Acad Sci U S A 93(9): 4278-4283. Liu, F., Y. Song and D. Liu (1999). 'Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA.' Gene Ther 6(7): 1258-1266. Liu, T., R. X. Wang, J. Han, C. Z. Hao, Y. L. Qiu, Y. Y. Yan, L. T. Li, N. L. Wang, J. Y. Gong, Y. Lu, M. H. Zhang, X. B. Xie, J. C. Yang, Y. J. You, J. Q. Li, A. S. Knisely, C. H. Borchers, V. Ling and J. S. Wang (2018). 'Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations.' Liver Int 38(9): 1676-1685. Liu, Y. H., C. C. Cheng, C. C. Ho, W. T. Chao, R. J. Pei, Y. H. Hsu, L. C. Ho, B. H. Shiu and Y. S. Lai (2011). 'Plectin deficiency on cytoskeletal disorganization and transformation of human liver cells in vitro.' Med Mol Morphol 44(1): 21-26. Liu, Y. H., C. C. Cheng, C. C. Ho, W. T. Chao, R. J. Pei, Y. H. Hsu, K. T. Yeh, L. C. Ho, M. C. Tsai and Y. S. Lai (2008). 'Degradation of plectin with modulation of cytokeratin 18 in human liver cells during staurosporine-induced apoptosis.' In Vivo 22(5): 543-548. Liu, Y. H., C. C. Ho, C. C. Cheng, W. T. Chao, R. J. Pei, Y. H. Hsu and Y. S. Lai (2011). 'Cytokeratin 18-mediated disorganization of intermediate filaments is induced by degradation of plectin in human liver cells.' Biochem Biophys Res Commun 407(3): 575-580. Ljubuncic, P., I. Yousef and A. Bomzon (2004). 'Cholemic transgenic mice: a novel animal model to investigate the effects of bile acids.' J Pharmacol Toxicol Methods 50(3): 231-235. Lobert, V. H. and H. Stenmark (2011). 'Cell polarity and migration: emerging role for the endosomal sorting machinery.' Physiology (Bethesda) 26(3): 171-180. Lobert, V. H. and H. Stenmark (2012). 'The ESCRT machinery mediates polarization of fibroblasts through regulation of myosin light chain.' J Cell Sci 125(Pt 1): 29-36. Lu, F. T., J. F. Wu, H. Y. Hsu, Y. H. Ni, M. H. Chang, C. I. Chao and H. L. Chen (2014). 'gamma-Glutamyl transpeptidase level as a screening marker among diverse etiologies of infantile intrahepatic cholestasis.' J Pediatr Gastroenterol Nutr 59(6): 695-701. Malhi, H. and M. Camilleri (2017). 'Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases.' Curr Opin Pharmacol 37: 80-86. Martinot, E., L. Sedes, M. Baptissart, J. M. Lobaccaro, F. Caira, C. Beaudoin and D. H. Volle (2017). 'Bile acids and their receptors.' Mol Aspects Med 56: 2-9. Matsubara, T., F. Li and F. J. Gonzalez (2013). 'FXR signaling in the enterohepatic system.' Mol Cell Endocrinol 368(1-2): 17-29. McInroy, L. and A. Maatta (2011). 'Plectin regulates invasiveness of SW480 colon carcinoma cells and is targeted to podosome-like adhesions in an isoform-specific manner.' Exp Cell Res 317(17): 2468-2478. Misra, S., P. Ujhazy, Z. Gatmaitan, L. Varticovski and I. M. Arias (1998). 'The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver.' J Biol Chem 273(41): 26638-26644. Misra, S., L. Varticovski and I. M. Arias (2003). 'Mechanisms by which cAMP increases bile acid secretion in rat liver and canalicular membrane vesicles.' Am J Physiol Gastrointest Liver Physiol 285(2): G316-324. Mochizuki, K., T. Kagawa, A. Numari, M. J. Harris, J. Itoh, N. Watanabe, T. Mine and I. M. Arias (2007). 'Two N-linked glycans are required to maintain the transport activity of the bile salt export pump (ABCB11) in MDCK II cells.' Am J Physiol Gastrointest Liver Physiol 292(3): G818-828. Molinaro, A., A. Wahlstrom and H. U. Marschall (2018). 'Role of Bile Acids in Metabolic Control.' Trends Endocrinol Metab 29(1): 31-41. Morotti, R. A., F. J. Suchy and M. S. Magid (2011). 'Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings.' Seminars in liver disease 31(1): 3-10. Moseley, R. H., W. Wang, H. Takeda, K. Lown, L. Shick, M. Ananthanarayanan and F. J. Suchy (1996). 'Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis.' Am J Physiol 271(1 Pt 1): G137-146. Muhlfeld, S., O. Domanova, T. Berlage, C. Stross, A. Helmer, V. Keitel, D. Haussinger and R. Kubitz (2012). 'Short-term feedback regulation of bile salt uptake by bile salts in rodent liver.' Hepatology 56(6): 2387-2397. Muller, M., T. Ishikawa, U. Berger, C. Klunemann, L. Lucka, A. Schreyer, C. Kannicht, W. Reutter, G. Kurz and D. Keppler (1991). 'ATP-dependent | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76492 | - |
dc.description.abstract | 人類的膽汁傳輸蛋白(Bile salt export pump,BSEP;基因為ABCB11)是一個具有十二個穿膜區塊(transmembrane domain)的膜蛋白,主要分布在肝細胞的膽小管膜(canalicular/apical membrane)上將膽鹽自肝細胞輸送進入膽道系統(biliary system)。相較於大、小鼠有其他的分子能代償其膽汁傳輸蛋白的功能缺損,人類的膽汁傳輸蛋白是膽小管膜上唯一能傳輸膽鹽的蛋白質。當人類的膽汁傳輸蛋白異常或功能缺損時,會造成一系列不同嚴重程度的膽汁滯留症(cholestasis),包括:第二型進行性家族性肝內膽汁滯留(progressive familial intrahepatic cholestasis type 2,PFIC2)、第二型良性反覆性肝內膽汁滯留(benign recurrent intrahepatic cholestasis type 2,BRIC2)、妊娠期肝內膽汁滯留症(intrahepatic cholestasis in pregnancy,ICP),以及藥物引起的肝臟受損(drug-induced liver injuries)。在許多藥物開發過程中,若會造成膽汁傳輸蛋白功能受到抑制或是影響膽汁傳輸蛋白在膽小管膜上表現時,也是造成該藥物開發失敗的主因之一。然而目前關於膽汁傳輸蛋白造成膽汁滯留的機制所知不多,特別是在臨上可以發現許多病人的膽汁傳輸蛋白無法在膽小管膜上表現,但是卻沒有膽汁傳輸蛋白基因上的突變。此外,在人類胎兒肝臟裡的膽汁傳輸蛋白分布與成人有顯著地不同。相較於成人肝細胞內的膽汁傳輸蛋白主要分布在膽小管膜上,胎兒肝細胞裡的膽汁傳輸蛋白卻只有部份在膽小管膜上,其他則散布在細胞質中。由這些觀察可以推測有些潛在的因子能直接或間接地調控膽汁傳輸蛋白在細胞內的分布與膽小管膜的定位(canalicular/apical targeting)。但是在這部分的相關研究相當有限。
本論文試圖探索能調控膽汁傳輸蛋白於細胞內的移動(subcellular trafficking)可能的膽汁傳輸蛋白交互作作用蛋白分子(interacting proteins),同時也企圖從疑似患有進行性家族性肝內膽汁滯留的病人檢體來找尋潛在的致病基因。在找尋可能的膽汁傳輸蛋白交互作用蛋白分子部份,利用人類膽汁傳輸蛋白的片段分子於人類胎兒肝臟cDNA基因庫(human fetal liver cDNA library)中進行酵母菌雙雜交系統分析,進而找到CHMP5為可能的膽汁傳輸蛋白交互作用分子。CHMP5已知參與細胞內endosomal sorting complex required for transport(ESCRT)subcomplex-III的組成。在體外培養細胞株以及小鼠中進行研究,同時以人類的胎兒肝臟與患有膽汁滯留的肝臟染色發現:膽汁傳輸蛋白若是與ESCRT的交互作用異常,很可能是導致膽汁傳輸蛋白於細胞質內異常停滯進而造成膽汁滯留疾病。同時這也是首次發現ESCRT參與膽汁傳輸蛋白於後高基氏體的傳送(post-Golgi trafficking),而且是在已知的Rab11上游。更進一步地發現肝細胞內已知膽汁傳輸蛋白所停留的胞器(subapical compartments,SACs),除了會有CHMP5以及另一個ESCRT-III分子LIP5外,這個仍諸多未知的胞器同時也有Rab5及Rab11的表現,所以這個胞器極有可能是所謂的早期/轉運胞內體(early/sorting endosome)。因此可以推測ESCRT所參與的膽汁傳輸蛋白於細胞內的移動是在膽汁傳輸蛋白離開高基氏體至轉運胞內體之間。 另一方面在找尋可能造成進行性家族性肝內膽汁滯留的基因部分,自一對膽汁滯留手足中發現一個全新的膽汁滯留基因PLEC。Plectin(PLEC,基因為PLEC)是一個細胞骨架連接蛋白(cytoskeleton linker protein)。膽汁傳輸蛋白在細胞內的運輸已知會受到細胞骨架以及細胞骨架上相關蛋白分子(cytoskeleton-associated proteins)影響。Plectin能聯結不同的細胞骨架(例如:角質蛋白)以維持肝細胞的結構。在帶有PLEC突變的膽汁滯留病人肝臟中發現其膽汁傳輸蛋白在膽小管膜上的表現嚴重受到影響,同時PLEC與角質蛋白第八型(Keratin 8,K8)的共同分布(co-localization)也降低。由膽汁傳輸蛋白於膽小管膜上的分布異常,同時血清中的膽鹽濃度異常增加,意味著PLEC突變可能藉由影響膽汁傳輸蛋白的膽小管膜定位或是可能扮演疾病修飾角色,進而造成膽汁滯留。 膽汁傳輸蛋白於膽小管膜上表現對其功能極為重要。本論文所運用的一些研究方式亦能應用於其他的膜蛋白的細胞內運輸與相關疾病的機制探索。同時,本論文中所發現的一些其他膽汁傳輸蛋白交作用分子及PLEC對膽汁滯留的機制值得更深入的探討與研究。 | zh_TW |
dc.description.abstract | The bile salt export pump (BSEP), encoded by the ABCB11 gene, is an apical/canalicular protein with 12 transmembrane domains and mediates bile salts from hepatocytes into the biliary system. BSEP is the only apical transporter for the bile salts in humans and, unlike rodents, no other genes could compensate for the loss of BSEP functions. Abnormalities of BSEP could lead to a spectrum of cholestatic diseases including the progressive familial intrahepatic cholestasis type 2, benign recurrent intrahepatic cholestasis, intrahepatic cholestasis in pregnancy, and drug-induced liver injuries. Defects in BSEP function and canalicular expression, such as cytoplasmic accumulation, are also pivotal events that have caused the failure of many newly developed drugs. However, the mechanism of BSEP-associated cholestasis is poorly understood, especially in patients with no detected BSEP mutations in the coding regions but having impaired apical targeting of BSEP. Moreover, BSEP in human fetal livers partially expressed at the canalicular membrane and in the cytoplasm, rather than majorly at the canalicular membrane in adult. These data suggested some underlying factors regulate the distribution and apical targeting of BSEP directly or in an indirect manner.
In this dissertation, I aimed to discover BSEP-interacting proteins that modulates the subcellular trafficking of BSEP and to search novel PFIC-associated genes. I used a human BSEP polypeptide as a bait to screen the human fetal liver cDNA library through yeast two-hybrid systems. Several BSEP-interacting candidates were uncovered. One of the BSEP-interacting candidates is charged multivesicular body protein 5 (CHMP5), a key endosomal protein complex required for transport subcomplex-III (ESCRT-III). Using in vitro and in vivo modals, cholestatic, and developmental human liver samples, BSEP aberrantly associating with ESCRTs may cause cytoplasmic retention of BSEP at the subapical compartments (SACs) in cholestatic diseases. These BSEP locating SACs had the expression of not only ESCRT molecules but also the two endosomal proteins Rab5 and Rab11. These findings suggested that these SACs are the early/sorting endosomes. Moreover, I provided the first example and new function of ESCRTs, in which ESCRTs involved in the post-Golgi trafficking of BSEP, which was upstream of Rab11 regulated apical cycling of BSEP. Therefore, ESCRTs mediated BSEP sorting from the trans-Golgi to the sorting endosomes. The last part of the dissertation described the discovery of a novel cholestatic gene, PLEC, associated by studying the samples from a pair of cholestasis siblings. Plectin (PLEC), encoded by PLEC, is a cytoskeleton linker protein, which linked different cytoskeletons to sustain the architecture of hepatocytes. PLEC mutated patients’ liver samples revealed impaired canalicular expression of BSEP and reduced co-localization of PLEC and the keratin 8 (K8). The impaired BSEP canalicular expression and elevated bile acid levels suggested that the PLEC mutations may either affect BSEP targeting and cause cholestasis, or be a disease modifier gene. Canalicular expression of BSEP is critical to BSEP function. The modus operandi of my work on the trafficking mechanism of BSEP could be easily applied to study all other transmembrane proteins for uncovering the etiologies of other important diseases. Besides, several BSEP-interacting candidates and the diseased mechanism of impaired BSEP trafficking in PLEC mutations are worthy to further study. | en |
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dc.description.tableofcontents | Contents i
誌謝 viii 摘要 x ABSTRACT xii Chapter 1 Background and specific aims 1 1.1. Cholestatic liver diseases 1 1.2. The function and composition of bile 1 1.3. Biosynthesis, homeostasis, and the enterohepatic circulation of bile acids 2 1.4. The transporters mediating the transfer of bile acids and other bile ingredients 5 1.5. Progressive intrahepatic cholestasis (PFIC) 6 1.6. The bile salt export pump (BSEP) is the canalicular bile acid transporter. 7 1.7. Developmental expression of BSEP/Bsep orthologs 11 1.8. Bile salt preferences of BSEP/Bsep orthologs 11 1.9. Abcb11/Bsep knockout animal models 12 1.10. Subcellular trafficking of BSEP 15 1.11. BSEP interacting proteins that participate in subcellular trafficking of BSEP 16 1.12. Research Questions and Niches 17 1.13. Hypothesis and specific aims 18 Chapter 2 Identification of BSEP-interacting proteins 20 2.1. Introduction 20 2.2. Materials and Methods 20 2.2.1. Reagents and chemicals 20 2.2.2. Plasmid construction 21 2.2.3. Yeast transformation, protein extraction, and 3-AT titration 21 2.2.4. The human fetal liver cDNA library 21 2.2.5. Yeast two-hybrid and β-galactosidase filter assays 22 2.2.6. Determination of cDNA identities 22 2.3. Results 23 2.3.1. The human BSEP polypeptide spanning amino acid 270-815 was used to search the BSEP-interacting proteins through yeast two-hybrid assays. 23 2.3.2. Approximate 15% of yeast colonies identified from yeast two-hybrid screening reveals strong β-galactosidase activity. 24 2.3.3. Analysis of yeast plasmid inserts by polymerase chain reaction 24 2.4. Summary 25 Chapter 3 The ESCRT machinery participates the post-Golgi trafficking of BSEP 26 3.1. Introduction 26 3.2. Materials and Methods 27 3.2.1. Human liver samples 27 3.2.2. Plasmid construction and transfection 27 3.2.3. Hydrodynamic injection of mice 28 3.2.4. Yeast two-hybrid screen and interaction assay 29 3.2.5. Cell culture 29 3.2.6. Temperature shift assay 29 3.2.7. Protein extraction and subcellular fractionation 29 3.2.8. Antibodies, immunoprecipitation, Western blotting and immunostaining 30 3.2.9. RNA interference and quantitative RT-PCR 31 3.2.10. Determination of total bile acids 32 3.2.11. Image acquisition and processing 32 3.2.12. Subcellular distribution index and canalicular targeting index 32 3.2.13. Statistical analysis 33 3.3. Results 33 3.3.1. The ESCRT-III CHMP5 interacts with BSEP. 33 3.3.2. Subapical BSEP localizes in CHMP5-positive subapical compartments. 34 3.3.3. Cholestatic human livers demonstrate aberrant subapical BSEP vesicles. 35 3.3.4. The canalicular targeting of BSEP is developmentally associated with CHMP5. 35 3.3.5. Aberrant interaction between BSEP mutants and CHMP5 affects the polarized trafficking of BSEP mutants. 36 3.3.6. CHMP5 regulates the apical targeting of BSEP and BSEP-mediated bile acid secretion. 38 3.3.7. K63-linked ubiquitination of BSEP is required for the BSEP apical-targeting via CHMP5 associated ESCRT machinery. 39 3.3.8. The ESCRT machinery affects the polarized trafficking of BSEP. 40 3.3.9. The ESCRT machinery is upstream of Rab11A to affect the post-Golgi trafficking of BSEP. 40 3.4. Summary 41 Chapter 4 Plectin mutations in progressive familial intrahepatic cholestasis 42 4.1. Introduction 42 4.2. Materials and Methods 43 4.2.1. Antibodies and Reagents 43 4.2.2. Immunofluorescence staining 43 4.2.3. Image acquisition 43 4.2.4. Analysis and Statistics of PLEC-K8 colocalization 44 4.3. Results 44 4.3.1. Case description 44 4.3.2. Plectin mutations are associated to PFIC 45 4.3.3. Decreased colocalization of PLEC and Keratin 8 (K8) in the liver samples of PLEC mutations 45 4.3.4. PLEC mutated livers show impaired canalicular expression of BSEP, dilated bile canaliculi, and distorted bile ducts. 46 4.4. Summary 46 Chapter 5 Discussion 48 5.1. Some underlying factors in human BSEP cDNA should be concerned. 48 5.2. Limited information of BSEP-interacting proteins as well as their mechanisms. 49 5.3. ESCRTs involve in post-Golgi trafficking of BSEP. 51 5.4. Both ESCRTs and endosomal Rab proteins participate in post-Golgi trafficking of apical proteins. 52 5.5. Defects in canalicular sorting of BSEP mutants may be caused by aberrant association with ESCRTs. 53 5.6. A proposed model of ESCRTs regulating the apical targeting of BSEP 55 5.7. Cholestatic liver diseases may be tangled with cytoskeleton disorganization and mis-sorting of canalicular transporters. 56 Chapter 6 Perspectives 60 6.1. Ubiquitination and deubiquitination of BSEP 60 6.2. The role of autophagy in canalicular expression of BSEP 61 6.3. COPA may mediate BSEP between ER and Golgi. 62 6.4. The cytoskeleton network and cytoskeleton-associated proteins in BSEP trafficking 62 6.5. To search underlying cholestasis-associated genes and to generate in vitro and in vivo models for studying BSEP and cholestasis are essential not only to disease mechanism but also to drug screening. 63 References 64 Tables 85 Table 1 Progressive familial intrahepatic cholestasis (PFIC)* 86 Table 2 A comparison of human, rat, mouse and skate BSEP/Bsep orthologs. 88 Table 3 Comparison of Km/*Ki values and bile salt transport between human, rat, mouse and skate membrane vesicles from the liver and the cell with ectopic BSEP/Bsep expression. 89 Table 4 The rank order of different bile salts transported by the Bsep ortholog of human, rat, mouse, and skate. 90 Table 5 A comarison of Abcb11/abcb11b knockout (KO) animal models 91 Table 6 Statistics and classification of β-galactosidase assays 92 Table 7 Classification of the cDNA inserts identified from the yeast two-hybrid screen for BSEP-interacting proteins. 93 Table 8 Classification of the cDNA inserts identified from the yeast two-hybrid screen for BSEP-interacting proteins. 95 Table 9 Clinical characteristics with serial laboratory data 96 Table 10 Jaundice-associated gene panel for target-gene enriched next-generation sequencing 97 Table 11 The Variants of the Five Genes Identified Using the Whole-Exome Sequencing from the Family Suspected of PFIC 98 Table 12 The Protein Encoded, Functions, Tissue Expression and Disease Association of the Gene Variants Identified in The Family of Progressive Familial Intrahepatic Cholestasis. 99 Figures 100 Figure 1 Etiologis of intrahepatic and extrahepatic cholestasis of congenital or acquired causes. 100 Figure 2 Functions of PFIC- and other cholestasis-associated proteins. 101 Figure 3 The synthesis pathways of bile acids. 102 Figure 4 The enterohepatic circulation and homeostasis of bile acids. 103 Figure 5 Milestons of BSEP/Bsep being characterized as the canalicular bile acid transporter (cBAT). 105 Figure 6 The line graph illustrates developmental expression of rat hepatic transporters. 107 Figure 7 Graphic illustration of subcellular trafficking of BSEP in hepatocytes. 108 Figure 8 The protein alignment of human, rat, and mouse BSEP orthologs spanning amino acids from 270 to 815. 109 Figure 9 The bait protein, BSEP (270-815), is unstable in yeast competent cells. 110 Figure 10 The bait protein, BSEP (270-815), is unstable in yeast competent cells. 111 Figure 11 The flow chart illustrates the search of BSEP-interacting proteins. 112 Figure 12 A representive result of β-galactosidase filter assays. 113 Figure 13 The ESCRT-III subunit CHMP5 co-localizes with BSEP in the subapical compartments of hepatocytes. 115 Figure 14 Aberrant subapical BSEP compartments in cholestatic human livers are CHMP5 positive. 117 Figure 15 Impaired polarized trafficking of BSEP-R487H and BSEP-N490D mutants in vivo and in vitro. 118 Figure 16 Aberrant association between CHMP5 and the two BSEP-R487H and BSEP-N490D mutants. 120 Figure 17 The protein expression and turnover of BSEP is unaffected with CHMP5 knockdown. 121 Figure 18 CHMP5 regulates the apical targeting of BSEP in vivo and in vitro. 122 Figure 19 CHMP5 indirectly regulates BSEP-mediated bile acid secretion. 124 Figure 20 BSEP is abundantly modified with K63-linked ubiquitination. 125 Figure 21 Both VPS4 molecules affect post-Golgi trafficking of BSEP. 127 Figure 22 VPS4 affecting apical targeting of BSEP is upstream of Rab11a. 128 Figure 23 The subapical compartments at which BSEP and CHMP5 are colocalized are Rab5 and Rab11 positive. 129 Figure 24 Proposed model of CHMP5-associated ESCRTs in BSEP canalicular-targeting. 130 Figure 25 The flow chart of whole-exome sequencing to explore novel PFIC-associated candidate genes. 131 Figure 26 The PLEC (NM_000436) mutations identified from the PFIC family. 132 Figure 27 Decreased colocalization of PLEC and K8 in the cholestatic liver samples of PLEC mutations. 133 Figure 28 The distorted bile ducts, disturbed canalicular targeting of BSEP and dilated ZO-1 positive bile canaliculi in the livers with PLEC mutation. 135 Appendix 136 Appendix Figure 1 Aberrant subapical BSEP compartments in a patient’s liver of neonatal hepatitis. 136 Appendix Figure 2 The ESCRT-III subunits CHMP5 and LIP5 co-localizes with BSEP-resident subapical compartments in adult human hepatocytes. 137 Appendix Figure 3 The total membrane-protein fraction contains the plasma-membrane plus organelle-membrane protein fractions. 138 Appendix Figure 4 BSEP is retained at aberrant CHMP5-positive subapical compartments in a transient cholestatic human liver sample. (Related to Figure 14D) 139 Appendix Figure 5 The canalicular targeting of BSEP is developmentally regulated and very likely associated with CHMP5 in human livers. 141 Appendix Figure 6 The glycosylation patterns of BSEP-R487H and BSEP-N490D are different from that of wild type BSEP. 142 Appendix Figure 7 CHMP5 might regulate BSEP ubiquitination in an indirect manner. 143 Appendix Table 1. The primer list 144 Appendix Table 2. All plasmids constructed and used in the disseration 152 Appendix Table 3. The publication during the PhD program 156 Abbreviations 157 | |
dc.language.iso | en | |
dc.title | 膽汁傳輸蛋白之肝細胞分布與膽汁滯留疾病之相關機轉 | zh_TW |
dc.title | The subcellular trafficking and targeting of bile salt export pump in hepatocytes and related mechanisms in cholestatic liver diseases | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 陳惠玲(Hui-Ling Chen) | |
dc.contributor.oralexamcommittee | 黃麗華(Lih-Hwa Hwang),賴明瑋(Ming-Wei Lai),周祖述(Tzuu-Shuh Jou),陳慧玲(Huey-Ling Chen),吳慧琳(Hui-Lin Wu) | |
dc.subject.keyword | 膽汁傳輸蛋白,ESCRT,胞內體,後高基氏體傳送,PLEC, | zh_TW |
dc.subject.keyword | BSEP,ESCRT,early/sorting endosome,post-Golgi trafficking,plectin, | en |
dc.relation.page | 164 | |
dc.identifier.doi | 10.6342/NTU201904328 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2019-11-27 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
dc.date.embargo-lift | 2022-03-13 | - |
顯示於系所單位: | 臨床醫學研究所 |
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