Comprehensive Physiology Wiley Online Library

Bile Proteome in Health and Disease

Full Article on Wiley Online Library



Abstract

The study of bile proteins could improve the understanding of physiological processes involved in the regulation of the hepato‐biliary system. Researchers have tried for years to investigate the bile proteome but, until recently, only a few tens of proteins were known. The advent of proteomics, availing of large‐scale analytical devices paired with potent bioinformatic resources, lately allowed the identification of thousands of proteins in bile. Nevertheless, the knowledge of their role in the hepato‐biliary system still represents almost a “blank page in the book of physiology.” In this review, we first guide the reader through the historical phases of the analysis of bile protein content, emphasizing the recent progresses achieved through the use of proteomic techniques. Thereafter, we deeply explore the involvement of bile proteins in health and disease, with a particular focus on the discovery of biomarkers for biliary tract malignancies. © 2014 American Physiological Society. Compr Physiol 4:91‐108, 2014.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Composition of hepatic and gallbladder bile (adapted from Ref. 55, with the permission of Elsevier).
Figure 2. Figure 2. Tissue specificity analysis of the complete catalogue of bile proteins.
Figure 3. Figure 3. Release mechanisms of proteins in bile. Release mechanisms of proteins in bile. (A) Paracellular pathway. Proteins enter bile canaliculi through tight junctions between adjacent hepatocytes. Low‐molecular weight proteins are favored. (B) Transcellular pathway, nonspecific endocytotic route. Proteins are first internalized by hepatocytes and then released into canaliculi. No discrimination is shown between low and high molecular weight proteins. Vesicles directly transferred to the canalicular membrane release proteins in their intact form (b1), while vesicles which fuse with lysosomes discharge protein fragments resulting from enzymatic digestion (b2). (C) Transcellular pathway, specific endocytotic route. The vesicular uptake of proteins is carried out through specific membrane receptors. Lysosomal (c2) and nonlysosomal (c1) endocytotic routes exist. In some cases, intact proteins linked to a proteolyzed fragment of their receptor may be released (c1).


Figure 1. Composition of hepatic and gallbladder bile (adapted from Ref. 55, with the permission of Elsevier).


Figure 2. Tissue specificity analysis of the complete catalogue of bile proteins.


Figure 3. Release mechanisms of proteins in bile. Release mechanisms of proteins in bile. (A) Paracellular pathway. Proteins enter bile canaliculi through tight junctions between adjacent hepatocytes. Low‐molecular weight proteins are favored. (B) Transcellular pathway, nonspecific endocytotic route. Proteins are first internalized by hepatocytes and then released into canaliculi. No discrimination is shown between low and high molecular weight proteins. Vesicles directly transferred to the canalicular membrane release proteins in their intact form (b1), while vesicles which fuse with lysosomes discharge protein fragments resulting from enzymatic digestion (b2). (C) Transcellular pathway, specific endocytotic route. The vesicular uptake of proteins is carried out through specific membrane receptors. Lysosomal (c2) and nonlysosomal (c1) endocytotic routes exist. In some cases, intact proteins linked to a proteolyzed fragment of their receptor may be released (c1).
References
 1. Abdallah AA , Krige JE , Bornman PC . Biliary tract obstruction in chronic pancreatitis. HPB (Oxford) 9: 421‐428, 2007.
 2. Adams DH , Wang L , Hubscher SG , Elias E , Neuberger JM . Soluble interleukin‐2 receptors in serum and bile of liver transplant recipients. Lancet 1: 469‐471, 1989.
 3. Alvaro D . Serum and bile biomarkers for cholangiocarcinoma. Curr Opin Gastroenterol 25: 279‐284, 2009.
 4. Alvaro D , Macarri G , Mancino MG , Marzioni M , Bragazzi M , Onori P , Corradini SG , Invernizzi P , Franchitto A , Attili AF , Gaudio E , Benedetti A . Serum and biliary insulin‐like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med 147: 451‐459, 2007.
 5. Arias IM. Liver function from Y to Z. J Clin Invest 122: 2763‐2764, 2012.
 6. Ayaru L , Stoeber K , Webster GJ , Hatfield AR , Wollenschlaeger A , Okoturo O , Rashid M , Williams G , Pereira SP . Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates. Br J Cancer 98: 1548‐1554, 2008.
 7. Bairoch A , Apweiler R , Wu CH , Barker WC , Boeckmann B , Ferro S , Gasteiger E , Huang H , Lopez R , Magrane M , Martin MJ , Natale DA , O'Donovan C , Redaschi N , Yeh LS . The Universal Protein Resource (UniProt). Nucleic Acids Res 33: D154‐159, 2005.
 8. Ballehaninna UK , Chamberlain RS . The clinical utility of serum CA 19‐9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol 3: 105‐119, 2012.
 9. Barbhuiya MA , Sahasrabuddhe NA , Pinto SM , Muthusamy B , Singh TD , Nanjappa V , Keerthikumar S , Delanghe B , Harsha HC , Chaerkady R , Jalaj V , Gupta S , Shrivastav BR , Tiwari PK , Pandey A . Comprehensive proteomic analysis of human bile. Proteomics 11: 4443‐4453, 2011.
 10. Benhamou PY , Vuillez JP , Halimi S , Meffre G , Bachelot I . Influence of metabolic disturbances of diabetes mellitus on serum CA 19‐9 tumor marker. Diabete Metab 17: 39‐43, 1991.
 11. Blechacz B , Gores GJ . Cholangiocarcinoma: Advances in pathogenesis, diagnosis, and treatment. Hepatology 48: 308‐321, 2008.
 12. Bonney GK , Craven RA , Prasad R , Melcher AF , Selby PJ , Banks RE . Circulating markers of biliary malignancy: Opportunities in proteomics? Lancet Oncol 9: 149‐158, 2008.
 13. Brockmann J , Emparan C , Hernandez CA , Sulkowski U , Dietl KH , Menzel J , Wolters H , Glodny B , Senninger N . Gallbladder bile tumor marker quantification for detection of pancreato‐biliary malignancies. Anticancer Res 20: 4941‐4947, 2000.
 14. Buffet C , Fourre C , Altman C , Prat F , Fritsch J , Choury A , Briantais MJ , Desgrez A , Etienne JP . Bile levels of carcino‐embryonic antigen in patients with hepatopancreatobiliary disease. Eur J Gastroenterol Hepatol 8: 131‐134, 1996.
 15. Carr S , Aebersold R , Baldwin M , Burlingame A , Clauser K , Nesvizhskii A . The need for guidelines in publication of peptide and protein identification data: Working Group on Publication Guidelines for Peptide and Protein Identification Data. Mol Cell Proteomics 3: 531‐533, 2004.
 16. Chapman R , Fevery J , Kalloo A , Nagorney DM , Boberg KM , Shneider B , Gores GJ . Diagnosis and management of primary sclerosing cholangitis. Hepatology 51: 660‐678, 2010.
 17. Charatcharoenwitthaya P , Enders FB , Halling KC , Lindor KD . Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 48: 1106‐1117, 2008.
 18. Chen B , Dong JQ , Chen YJ , Wang JM , Tian J , Wang CB , Zou SQ . Two‐dimensional electrophoresis for comparative proteomic analysis of human bile. Hepatobiliary Pancreat Dis Int 6: 402‐406, 2007.
 19. Chen CY , Shiesh SC , Tsao HC , Lin XZ . The assessment of biliary CA 125, CA 19‐9 and CEA in diagnosing cholangiocarcinoma—the influence of sampling time and hepatolithiasis. Hepatogastroenterology 49: 616‐620, 2002.
 20. Chen CY , Tsai WL , Wu HC , Syu MJ , Wu CC , Shiesh SC . Diagnostic role of biliary pancreatic elastase for cholangiocarcinoma in patients with cholestasis. Clin Chim Acta 390: 82‐89, 2008.
 21. Chowrimootoo GF , Seymour CA . The role of caeruloplasmin in copper excretion. Biochem Soc Trans 22: 190S, 1994.
 22. Chuang SC , Hsi E , Lee KT . Mucin genes in gallstone disease. Clin Chim Acta 413: 1466‐1471, 2012.
 23. Chuang YH , Lan RY , Gershwin ME . The immunopathology of human biliary cell epithelium. Semin Immunopathol 31: 323‐331, 2009.
 24. Claassen M . Inference and validation of protein identifications. Mol Cell Proteomics, 2012 Nov;11(11):1097‐1104. doi: 10.1074/ mcp.R111.014795. Epub 2012 Aug 3.
 25. Clavien P‐A , Baillie J . Diseases of the Gallbladder and Bile Ducts : Diagnosis and Treatment. Malden, Massachusetts: Blackwell, 2006.
 26. Coleman R . Biochemistry of bile secretion. Biochem J 244: 249‐261, 1987.
 27. Davidoff AM , Pappas TN , Murray EA , Hilleren DJ , Johnson RD , Baker ME , Newman GE , Cotton PB , Meyers WC . Mechanisms of major biliary injury during laparoscopic cholecystectomy. Ann Surg 215: 196‐202, 1992.
 28. Dhar DK , Olde Damink SW , Brindley JH , Godfrey A , Chapman MH , Sandanayake NS , Andreola F , Mazurek S , Hasan T , Malago M , Pereira SP . Pyruvate kinase M2 is a novel diagnostic marker and predicts tumor progression in human biliary tract cancer. Cancer 119: 575‐585, 2013.
 29. Dive C , Heremans JF . Nature and origin of the proteins of bile. I. A comparative analysis of serum and bile proteins in man. Eur J Clin Invest 4: 235‐239, 1974.
 30. Dive C , Nadalini RA , Vaerman JP , Heremans JF . Origin and nature of the proteins of bile. II. A comparative analysis of serum, hepatic lymph and bile proteins in the dog. Eur J Clin Invest 4: 241‐246, 1974.
 31. Dorrance HR , McGregor JR , McAllister EJ , O'Dwyer PJ . Bile carcinoembryonic antigen levels and occult hepatic metastases from colorectal cancer. Dis Colon Rectum 43: 1292‐1295; discussion 1295‐1296, 2000.
 32. Dove A . Proteomics: translating genomics into products? Nat Biotechnol 17: 233‐236, 1999.
 33. Dumonceau JM . Sampling at ERCP for cyto‐ and histopathologicical examination. Gastrointest Endosc Clin N Am. 2012 Jul;22(3):461‐477. doi: 10.1016/j.giec.2012.05.006. Epub 2012 Jun 13.
 34. Dumonceau JM , Koessler T , van Hooft JE , Fockens P . Endoscopic ultrasonography‐guided fine needle aspiration: Relatively low sensitivity in the endosonographer population. World J Gastroenterol 18: 2357‐2363, 2012.
 35. Dumonceau JM , Macias Gomez C , Casco C , Genevay M , Marcolongo M , Bongiovanni M , Morel P , Majno P , Hadengue A . Grasp or brush for biliary sampling at endoscopic retrograde cholangiography? A blinded randomized controlled trial. Am J Gastroenterol 103: 333‐340, 2008.
 36. Dumonceau JM , Polkowski M , Larghi A , Vilmann P , Giovannini M , Frossard JL , Heresbach D , Pujol B , Fernandez‐Esparrach G , Vazquez‐Sequeiros E , Gines A . Indications, results, and clinical impact of endoscopic ultrasound (EUS)‐guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 43: 897‐912, 2011.
 37. Duncan D , Prodduturi N , Zhang B . WebGestalt2: an updated and expanded version of the Web‐based Gene Set Analysis Toolkit. BMC Bioinformatics 11: 10, 2010.
 38. Esteller A . Physiology of bile secretion. World J Gastroenterol 14: 5641‐5649, 2008.
 39. Evans WH , Kremmmer T , Culvenor JG . Role of membranes in bile formation. Comparison of the composition of bile and a liver bile‐canalicular plasma‐membrane subfraction. Biochem J 154: 589‐595, 1976.
 40. Farid SG , Craven RA , Peng J , Bonney GK , Perkins DN , Selby PJ , Rajendra Prasad K , Banks RE . Shotgun proteomics of human bile in hilar cholangiocarcinoma. Proteomics 11: 2134‐2138, 2011.
 41. Farina A, Dumonceau JM, Antinori P, Annessi‐Ramseyer I, Frossard JL, Hochstrasser DF, Delhaye M, Lescuyer P. Bile carcinoembryonic cell adhesion molecule 6 (CEAM6) as a biomarker of malignant biliary stenoses. Biochim Biophys Acta. 2013 Jun 24. pii: S1570‐9639(13)00241‐0. doi: 10.1016/j.bbapap.2013.06.010. [Epub ahead of print]
 42. Farina A , Dumonceau JM , Delhaye M , Frossard JL , Hadengue A , Hochstrasser DF , Lescuyer P . A step further in the analysis of human bile proteome. J Proteome Res 10: 2047‐2063, 2011.
 43. Farina A , Dumonceau JM , Frossard JL , Hadengue A , Hochstrasser DF , Lescuyer P . Proteomic analysis of human bile from malignant biliary stenosis induced by pancreatic cancer. J Proteome Res 8: 159‐169, 2009.
 44. Farina A , Dumonceau JM , Lescuyer P . Proteomic analysis of human bile and potential applications for cancer diagnosis. Expert Rev Proteomics 6: 285‐301, 2009.
 45. Farnaud S , Evans RW . Lactoferrin—a multifunctional protein with antimicrobial properties. Mol Immunol 40: 395‐405, 2003.
 46. Ferrone CR , Finkelstein DM , Thayer SP , Muzikansky A , Fernandez‐delCastillo C , Warshaw AL . Perioperative CA19‐9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol 24: 2897‐2902, 2006.
 47. Finzi L , Barbu V , Burgel PR , Mergey M , Kirkwood KS , Wick EC , Scoazec JY , Peschaud F , Paye F , Nadel JA , Housset C . MUC5AC, a gel‐forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder. Am J Pathol 169: 2031‐2041, 2006.
 48. Foucaud L , Grillasca J , Niot I , Domingo N , Lafont H , Planells R , Besnard P . Output of liver fatty acid‐binding protein (L‐FABP) in bile. Biochim Biophys Acta 1436: 593‐599, 1999.
 49. Frikart L , Fournier K , Mach JP , Givel JC . Potential value of biliary CEA assay in early detection of colorectal adenocarcinoma liver metastases. Eur J Surg Oncol 21: 276‐279, 1995.
 50. Frossard JL , Morel PM . Detection and management of bile duct stones. Gastrointest Endosc 72: 808‐816, 2010.
 51. Furukawa M , Ito S , Nakata T , Yamada R , Sakai T , Maeda S , Morinaga T , Chiba K , Itoshe K , Ohtsubo M , Ohno Y, Abiru H. A study of carcinoembryonic antigen levels in the bile of patients with carcinoma of pancreas and biliary system. Nihon Shokakibyo Gakkai Zasshi 81: 2561‐2567, 1984.
 52. Goonetilleke KS , Siriwardena AK . Systematic review of carbohydrate antigen (CA 19‐9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 33: 266‐270, 2007.
 53. Gouma DJ , Go PM . Bile duct injury during laparoscopic and conventional cholecystectomy. J Am Coll Surg 178: 229‐233, 1994.
 54. Groen AK , Van Wijland MJ , Frederiks WM , Smit JJ , Schinkel AH , Oude Elferink RP . Regulation of protein secretion into bile: Studies in mice with a disrupted mdr2 p‐glycoprotein gene. Gastroenterology 109: 1997‐2006, 1995.
 55. Guerrier L , Claverol S , Finzi L , Paye F , Fortis F , Boschetti E , Housset C . Contribution of solid‐phase hexapeptide ligand libraries to the repertoire of human bile proteins. J Chromatogr A 1176: 192‐205, 2007.
 56. Hall JE , Guyton AC . Guyton and Hall Textbook of Medical Physiology. Philadelphia, Pa.: Saunders/Elsevier, 2011.
 57. Hall JG , Pappas TN . Current management of biliary strictures. J Gastrointest Surg 8: 1098‐1110, 2004.
 58. Hammel P , Levy P , Voitot H , Levy M , Vilgrain V , Zins M , Flejou JF , Molas G , Ruszniewski P , Bernades P . Preoperative cyst fluid analysis is useful for the differential diagnosis of cystic lesions of the pancreas. Gastroenterology 108: 1230‐1235, 1995.
 59. Harada K , Chiba M , Okamura A , Hsu M , Sato Y , Igarashi S , Ren XS , Ikeda H , Ohta H , Kasashima S , Kawashima A , Nakanuma Y . Monocyte chemoattractant protein‐1 derived from biliary innate immunity contributes to hepatic fibrogenesis. J Clin Pathol 64: 660‐665, 2011.
 60. Harada K , Nakanuma Y . Biliary innate immunity: Function and modulation. Mediators Inflamm 2010, 2010. pii: 373878. doi: 10.1155/2010/373878. Epub 2010 Jul 27.
 61. He C , Fischer S , Meyer G , Muller I , Jungst D . Two‐dimensional electrophoretic analysis of vesicular and micellar proteins of gallbladder bile. J Chromatogr A 776: 109‐115, 1997.
 62. Heinrich S , Clavien PA . Ampullary cancer. Curr Opin Gastroenterol 26: 280‐285, 2010.
 63. Henzel WJ , Watanabe C , Stults JT . Protein identification: The origins of peptide mass fingerprinting. J Am Soc Mass Spectrom 14: 931‐942, 2003.
 64. Ho KJ . Biliary electrolytes and enzymes in patients with and without gallstones. Dig Dis Sci 41: 2409‐2416, 1996.
 65. Holan KR , Holzbach RT , Hermann RE , Cooperman AM , Claffey WJ . Nucleation time: A key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 77: 611‐617, 1979.
 66. Holdsworth G , Coleman R . Enzyme profiles of mammalian bile. Biochim Biophys Acta 389: 47‐50, 1975.
 67. Holzbach RT , Kibe A , Thiel E , Howell JH , Marsh M , Hermann RE . Biliary proteins. Unique inhibitors of cholesterol crystal nucleation in human gallbladder bile. J Clin Invest 73: 35‐45, 1984.
 68. Howell DA , Parsons WG , Jones MA , Bosco JJ , Hanson BL . Complete tissue sampling of biliary strictures at ERCP using a new device. Gastrointest Endosc 43: 498‐502, 1996.
 69. Hu Q , Noll RJ , Li H , Makarov A , Hardman M , Graham Cooks R . The Orbitrap: A new mass spectrometer. J Mass Spectrom 40: 430‐443, 2005.
 70. Inui K , Yoshino J , Miyoshi H . Differential diagnosis and treatment of biliary strictures. Clin Gastroenterol Hepatol 7: S79‐83, 2009.
 71. Ishida H , Yoshinaga K , Gonda T , Ando M , Hojo I , Fukunari H , Iwama T , Mishima Y . Biliary carcinoembryonic antigen levels can predict metachronous liver metastasis of colorectal cancer. Anticancer Res 20: 523‐526, 2000.
 72. Jackson GD , Dai Y , Sewell WA . Bile mediates intestinal pathology in endotoxemia in rats. Infect Immun 68: 4714‐4719, 2000.
 73. Jailwala J , Fogel EL , Sherman S , Gottlieb K , Flueckiger J , Bucksot LG , Lehman GA . Triple‐tissue sampling at ERCP in malignant biliary obstruction. Gastrointest Endosc 51: 383‐390, 2000.
 74. Jenssen H , Hancock RE . Antimicrobial properties of lactoferrin. Biochimie 91: 19‐29, 2009.
 75. Jirsa M , Groen AK . Role of biliary proteins and non‐protein factors in kinetics of cholesterol crystallisation and gallstone growth. Front Biosci 6: E154‐167, 2001.
 76. Jones AL , Burwen SJ . Pathways and functions of biliary protein secretion. In: Schultz SG , Rauner BB , Wood JD , editors. The Gastrointestinal System. Bethesda, New York: Oxford University Press, 1989, p. 663‐675.
 77. Jones AL , Renston RH , Burwen SJ . Uptake and intracellular disposition of plasma‐derived proteins and apoproteins by hepatocytes. Prog Liver Dis 7: 51‐69, 1982.
 78. Kaetzel CS . The polymeric immunoglobulin receptor: Bridging innate and adaptive immune responses at mucosal surfaces. Immunol Rev 206: 83‐99, 2005.
 79. Kaetzel CS , Robinson JK , Chintalacharuvu KR , Vaerman JP , Lamm ME . The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: A local defense function for IgA. Proc Natl Acad Sci U S A 88: 8796‐8800, 1991.
 80. Ker CG , Chen JS , Lee KT , Sheen PC , Wu CC . Assessment of serum and bile levels of CA19‐9 and CA125 in cholangitis and bile duct carcinoma. J Gastroenterol Hepatol 6: 505‐508, 1991.
 81. Ker CG , Wu CC , Chen JS , Hou MF , Lee KT , Sheen PC . A study of CEA, CA 19‐9 and CA 125 in biliary tract diseases. Gaoxiong Yi Xue Ke Xue Za Zhi 5: 107‐113, 1989.
 82. Keulemans YC , Mok KS , de Wit LT , Gouma DJ , Groen AK . Hepatic bile versus gallbladder bile: A comparison of protein and lipid concentration and composition in cholesterol gallstone patients. Hepatology 28: 11‐16, 1998.
 83. Kim C , Aono S , Marubashi S , Wada H , Kobayashi S , Eguchi H , Takeda Y , Tanemura M , Okumura N , Takao T , Doki Y , Mori M , Nagano H . Significance of alanine aminopeptidase N (APN) in bile in the diagnosis of acute cellular rejection after liver transplantation. J Surg Res 175: 138‐148, 2012.
 84. Kim MJ , Kim EK , Kim BM , Kwak JY , Lee EJ , Park CS , Cheong WY , Nam KH . Thyroglobulin measurement in fine‐needle aspirate washouts: The criteria for neck node dissection for patients with thyroid cancer. Clin Endocrinol (Oxf) 70: 145‐151, 2009.
 85. Kitajima Y , Ohara H , Nakazawa T , Ando T , Hayashi K , Takada H , Tanaka H , Ogawa K , Sano H , Togawa S , Naito I , Hirai M , Ueno K , Ban T , Miyabe K , Yamashita H , Yoshimura N , Akita S , Gotoh K , Joh T . Usefulness of transpapillary bile duct brushing cytology and forceps biopsy for improved diagnosis in patients with biliary strictures. J Gastroenterol Hepatol 22: 1615‐1620, 2007.
 86. Konomi K , Nakamura K , Tobimatsu M , Saito S , Toyoda K , Yasunami Y . Identification of carcinoembryonic antigen (CEA) in bile of patients with malignant biliary tract disease. Jpn J Surg 12: 184‐190, 1982.
 87. Koopmann J , Thuluvath PJ , Zahurak ML , Kristiansen TZ , Pandey A , Schulick R , Argani P , Hidalgo M , Iacobelli S , Goggins M , Maitra A . Mac‐2‐binding protein is a diagnostic marker for biliary tract carcinoma. Cancer 101: 1609‐1615, 2004.
 88. Koprowski H , Steplewski Z , Mitchell K , Herlyn M , Herlyn D , Fuhrer P . Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic Cell Genet 5: 957‐971, 1979.
 89. Korner T , Kropf J , Hackler R , Brenzel A , Gressner AM . Fibronectin in human bile fluid for diagnosis of malignant biliary diseases. Hepatology 23: 423‐428, 1996.
 90. Korolenko TA , Savchenko NG , Yuz'ko JV , Alexeenko TV , Sorochinskaya NV . Activity of lysosomal enzymes in the bile and serum of mice with intrahepatic cholestasis. Bull Exp Biol Med 145: 560‐563, 2008.
 91. Kristiansen TZ , Bunkenborg J , Gronborg M , Molina H , Thuluvath PJ , Argani P , Goggins MG , Maitra A , Pandey A . A proteomic analysis of human bile. Mol Cell Proteomics 3: 715‐728, 2004.
 92. Kristiansen TZ , Maitra A , Pandey A . Proteomics of human bile. In: Thongboonkerd V , editor. Proteomics of Human Body Fluids : Principles, Methods, and Applications. Totowa, N.J.: Humana Press, 2007, pp. 399‐414.
 93. Kruglov EA , Nathanson RA , Nguyen T , Dranoff JA . Secretion of MCP‐1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am J Physiol Gastrointest Liver Physiol 290: G765‐771, 2006.
 94. Kuno N , Kurimoto K , Fukushima M , Hayakawa T , Shibata T , Suzuki T , Sakakibara A , Katada N , Nakano S , Takayama T . Effectiveness of multivariate analysis of tumor markers in diagnosis of pancreatic carcinoma: A prospective study in multiinstitutions. Pancreas 9: 725‐730, 1994.
 95. Kurumiya Y , Nimura Y , Takeuchi E , Nozawa K , Nagino M , Hayata A , Maeda A , Yoshida S . Active form of human hepatocyte growth factor is excreted into bile after hepatobiliary resection. J Hepatol 30: 22‐28, 1999.
 96. Lang T , Krams SM , Berquist W , Cox KL , Esquivel CO , Martinez OM . Elevated biliary interleukin 5 as an indicator of liver allograft rejection. Transpl Immunol 3: 291‐298, 1995.
 97. Lankisch TO , Metzger J , Negm AA , Vosskuhl K , Schiffer E , Siwy J , Weismuller TJ , Schneider AS , Thedieck K , Baumeister R , Zurbig P , Weissinger EM , Manns MP , Mischak H , Wedemeyer J . Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis. Hepatology 53: 875‐884, 2011.
 98. LaRusso NF . Proteins in bile: How they get there and what they do. Am J Physiol 247: G199‐205, 1984.
 99. Lee SP , LaMont JT , Carey MC . Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. J Clin Invest 67: 1712‐1723, 1981.
 100. Lemaitrecoelho I , Jackson GDF , Vaerman JP . Rat bile as a convenient source of secretory Iga and free secretory component. Eur J Immunol 7: 588‐590, 1977.
 101. Lescuyer P , Farina A , Hochstrasser DF . Proteomics in clinical chemistry: Will it be long? Trends Biotechnol 28: 225‐229, 2010.
 102. Li D , Xie K , Wolff R , Abbruzzese JL . Pancreatic cancer. Lancet 363: 1049‐1057, 2004.
 103. Li Destri G , Curreri R , Lanteri R , Gagliano G , Rodolico M , Di Cataldo A , Puleo S . Biliary carcinoembryonic antigen in the diagnosis of occult hepatic metastases from colorectal cancer. J Surg Oncol 81: 8‐11, 2002.
 104. Li Destri G , Lanteri R , Santangelo M , Torrisi B , Di Cataldo A , Puleo S . Can biliary carcinoembryonic antigen identify colorectal cancer patients with occult hepatic metastases? World J Surg 30: 1494‐1499, 2006.
 105. Maeda A , Nagino M , Takeuchi E , Sano T , Kurumiya Y , Nimura Y . Interleukin 6 in bile as an indicator of liver function after hepatectomy in patients with biliary tract carcinoma. Br J Surg 86: 458‐464, 1999.
 106. Makarov A , Denisov E , Lange O . Performance evaluation of a high‐field Orbitrap mass analyzer. J Am Soc Mass Spectrom 20: 1391‐1396, 2009.
 107. Makarov A , Denisov E , Lange O , Horning S . Dynamic range of mass accuracy in LTQ Orbitrap hybrid mass spectrometer. J Am Soc Mass Spectrom 17: 977‐982, 2006.
 108. Matull WR , Andreola F , Loh A , Adiguzel Z , Deheragoda M , Qureshi U , Batra SK , Swallow DM , Pereira SP . MUC4 and MUC5AC are highly specific tumour‐associated mucins in biliary tract cancer. Br J Cancer 98: 1675‐1681, 2008.
 109. Menias CO , Surabhi VR , Prasad SR , Wang HL , Narra VR , Chintapalli KN . Mimics of cholangiocarcinoma: spectrum of disease. Radiographics 28: 1115‐1129, 2008.
 110. Mizuguchi Y , Specht S , Isse K , Lunz JG 3rd , Demetris AJ. Biliary epithelial cells. In: Monga SPS , editor. Molecular Pathology of Liver Diseases. New York Dordrecht Heidelberg London: Springer, 2011, pp. 27‐51.
 111. Molina LM , Díez M , Cava MT , Maestro ML , Ortega MD , Mendíz JG , Prego A , De Diego JA , Balibrea JL . Tumor markers in pancreatic cancer: a comparative clinical study between CEA, CA 19‐9 and CA 50. Int J Biol Markers 5: 127‐132, 1990.
 112. Montgomery RC , Hoffma JP , Ross EA , Riley LB , Ridge JA , Eisenberg BL . Biliary CA 19‐9 values correlate with the risk of hepatic metastases in patients with adenocarcinoma of the pancreas. J Gastrointest Surg 2: 28‐35, 1998.
 113. Moura RM , Matos D , Galvao Filho MM , D'Ippolito G , Sjzenfeld J , Giuliano LM . Value of CEA level determination in gallbladder bile in the diagnosis of liver metastases secondary to colorectal adenocarcinoma. Sao Paulo Med J 119: 110‐113, 2001.
 114. Mullock BM , Dobrota M , Hinton RH . Sources of the proteins of rat bile. Biochim Biophys Acta 543: 497‐507, 1978.
 115. Mullock BM , Shaw LJ , Fitzharris B , Peppard J , Hamilton MJ , Simpson MT , Hunt TM , Hinton RH . Sources of proteins in human bile. Gut 26: 500‐509, 1985.
 116. Nakeeb A , Lipsett PA , Lillemoe KD , Fox‐Talbot MK , Coleman J , Cameron JL , Pitt HA . Biliary carcinoembryonic antigen levels are a marker for cholangiocarcinoma. Am J Surg 171: 147‐152; discussion 152‐143, 1996.
 117. Nehls O , Gregor M , Klump B . Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 24: 139‐154, 2004.
 118. Ohshio G , Manabe T , Watanabe Y , Endo K , Kudo H , Suzuki T , Tobe T . Comparative studies of DU‐PAN‐2, carcinoembryonic antigen, and CA19‐9 in the serum and bile of patients with pancreatic and biliary tract diseases: evaluation of the influence of obstructive jaundice. Am J Gastroenterol 85: 1370‐1376, 1990.
 119. Okada N , Ishida H , Murata N , Hashimoto D , Seyama Y , Kubota S . Matrix metalloproteinase‐2 and ‐9 in bile as a marker of liver metastasis in colorectal cancer. Biochem Biophys Res Commun 288: 212‐216, 2001.
 120. Osnes T , Sandstad O , Skar V , Osnes M . beta‐Glucuronidase in common duct bile, methodological aspects, variation of pH optima and relation to gallstones. Scand J Clin Lab Invest 57: 307‐315, 1997.
 121. Osnes T , Sandstad O , Skar V , Osnes M , Kierulf P . Total protein in common duct bile measured by acetonitrile precipitation and a micro bicinchoninic acid (BCA) method. Scand J Clin Lab Invest 53: 757‐763, 1993.
 122. Paganuzzi M , Onetto M , de Paoli M , Castagnola M , de Salvo L , Civalleri D , Grossi CE . Carcinoembryonic antigen (CEA) in serum and bile of colorectal cancer patients with or without detectable liver metastases. Anticancer Res 14: 1409‐1412, 1994.
 123. Pasanen PA , Eskelinen M , Partanen K , Pikkarainen P , Penttilä I , Alhava E . A prospective study of serum tumour markers carcinoembryonic antigen, carbohydrate antigens 50 and 242, tissue polypeptide antigen and tissue polypeptide specific antigen in the diagnosis of pancreatic cancer with special reference to multivariate diagnostic score. Br J Cancer 69: 562‐565, 1994.
 124. Pascher A , Neuhaus P . Bile duct complications after liver transplantation. Transpl Int 18: 627‐642, 2005.
 125. Patel T . Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33: 1353‐1357, 2001.
 126. Paul MA , Visser JJ , Mulder C , van Kamp GJ , Cuesta MA , Meijer S . The use of biliary CEA measurements in the diagnosis of recurrent colorectal cancer. Eur J Surg Oncol 23: 419‐423, 1997.
 127. Petit JM , Vaillant G , Olsson NO , Guignier F , Collignon S , Verges B , Brun JM . Elevated serum CA19‐9 levels in poorly controlled diabetic patients. Relationship with Lewis blood group. Gastroenterol Clin Biol 18: 17‐20, 1994.
 128. Phalipon A , Cardona A , Kraehenbuhl JP , Edelman L , Sansonetti PJ , Corthesy B . Secretory component: a new role in secretory IgA‐mediated immune exclusion in vivo. Immunity 17: 107‐115, 2002.
 129. Picotti P , Aebersold R . Selected reaction monitoring‐based proteomics: Workflows, potential, pitfalls and future directions. Nat Methods 9: 555‐566, 2012.
 130. Ponchon T , Gagnon P , Berger F , Labadie M , Liaras A , Chavaillon A , Bory R . Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: Results of a prospective study. Gastrointest Endosc 42: 565‐572, 1995.
 131. Portincasa P , Moschetta A , Palasciano G . Cholesterol gallstone disease. Lancet 368: 230‐239, 2006.
 132. Pugliese V , Conio M , Nicolo G , Saccomanno S , Gatteschi B . Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: A prospective study. Gastrointest Endosc 42: 520‐526, 1995.
 133. Reinhard L , Rupp C , Riedel HD , Ruppert T , Giese T , Flechtenmacher C , Weiss KH , Kloeters‐Plachky P , Stremmel W , Schirmacher P , Sauer P , Gotthardt DN . S100A9 is a biliary protein marker of disease activity in primary sclerosing cholangitis. PLoS One 7: e29821, 2012.
 134. Renston RH , Maloney DG , Jones AL , Hradek GT , Wong KY , Goldfine ID . Bile secretory apparatus: Evidence for a vesicular transport mechanism for proteins in the rat, using horseradish peroxidase and [125I]insulin. Gastroenterology 78: 1373‐1388, 1980.
 135. Reuben A . Biliary proteins. Hepatology 4: 46S‐50S, 1984.
 136. Robic S , Linscott KB , Aseem M , Humphreys EA , McCartha SR . Bile acids as modulators of enzyme activity and stability. Protein J 30: 539‐545, 2011.
 137. Sato Y , Harada K , Sasaki M , Yasaka T , Nakanuma Y . Heat shock proteins 27 and 70 are potential biliary markers for the detection of cholangiocarcinoma. Am J Pathol 180: 123‐130, 2012.
 138. Saucan L , Palade GE . Differential colchicine effects on the transport of membrane and secretory proteins in rat hepatocytes in vivo: Bipolar secretion of albumin. Hepatology 15: 714‐721, 1992.
 139. Schnekenburger J , Schick V , Kruger B , Manitz MP , Sorg C , Nacken W , Kerkhoff C , Kahlert A , Mayerle J , Domschke W , Lerch MM . The calcium binding protein S100A9 is essential for pancreatic leukocyte infiltration and induces disruption of cell‐cell contacts. J Cell Physiol 216: 558‐567, 2008.
 140. Scigelova M , Makarov A . Orbitrap mass analyzer—overview and applications in proteomics. Proteomics 6(Suppl 2): 16‐21, 2006.
 141. Shaib YH , Davila JA , McGlynn K , El‐Serag HB . Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 40: 472‐477, 2004.
 142. Shanbhogue AK , Tirumani SH , Prasad SR , Fasih N , McInnes M . Benign biliary strictures: A current comprehensive clinical and imaging review. AJR Am J Roentgenol 197: W295‐306, 2011.
 143. Shen J , Wang W , Wu J , Feng B , Chen W , Wang M , Tang J , Wang F , Cheng F , Pu L , Tang Q , Wang X , Li X . Comparative proteomic profiling of human bile reveals SSP411 as a novel biomarker of cholangiocarcinoma. PLoS One 7: e47476, 2012.
 144. Siegel R , Ward E , Brawley O , Jemal A . Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61: 212‐236, 2011.
 145. Smathers RL , Petersen DR . The human fatty acid‐binding protein family: Evolutionary divergences and functions. Hum Genomics 5: 170‐191, 2011.
 146. Song KH , Ellis E , Strom S , Chiang JY . Hepatocyte growth factor signaling pathway inhibits cholesterol 7alpha‐hydroxylase and bile acid synthesis in human hepatocytes. Hepatology 46: 1993‐2002, 2007.
 147. Stark M , Jornvall H , Johansson J . Isolation and characterization of hydrophobic polypeptides in human bile. Eur J Biochem 266: 209‐214, 1999.
 148. Stavropoulos S , Larghi A , Verna E , Battezzati P , Stevens P . Intraductal ultrasound for the evaluation of patients with biliary strictures and no abdominal mass on computed tomography. Endoscopy 37: 715‐721, 2005.
 149. Sugiyama M , Atomi Y , Wada N , Kuroda A , Muto T . Endoscopic transpapillary bile duct biopsy without sphincterotomy for diagnosing biliary strictures: A prospective comparative study with bile and brush cytology. Am J Gastroenterol 91: 465‐467, 1996.
 150. Sumiyoshi K , Andoh A , Fujiyama Y , Sakumoto H , Bamba T . Characterization of complement C3, C4, and factor B molecules in human bile. J Gastroenterol 32: 230‐235, 1997.
 151. Suzuki H , Iyomasa S , Nimura Y , Yoshida S . Internal biliary drainage, unlike external drainage, does not suppress the regeneration of cholestatic rat liver after partial hepatectomy. Hepatology 20: 1318‐1322, 1994.
 152. Swobodnik W , Ditschuneit H , Soloway RD . Gallstone Disease : Pathophysiology and Therapeutic Approaches. Berlin; New York: Springer‐Verlag, 1990.
 153. Tatsuta M , Yamamura H , Yamamoto R , Morii T , Okuda S , Tamura H . Carcinoembryonic antigen in the bile in patients with pancreatic and biliary cancer. Correlation with cytology and percutaneous transhepatic cholangiography. Cancer 50: 2903‐2909, 1982.
 154. Teng PN , Bateman NW , Hood BL , Conrads TP . Advances in proximal fluid proteomics for disease biomarker discovery. J Proteome Res 9: 6091‐6100, 2010.
 155. Tonshoff B , David‐Neto E , Ettenger R , Filler G , van Gelder T , Goebel J , Kuypers DR , Tsai E , Vinks AA , Weber LT , Zimmerhackl LB . Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev (Orlando) 25: 78‐89, 2011.
 156. Umeshita K , Monden M , Tono T , Hasuike Y , Kanai T , Gotoh M , Mori T , Seu P , Shaked A , Busuttil RW . Interleukin‐6 in bile as a marker of allograft rejection following liver transplantation in man. Transplant Proc 24: 1462‐1464, 1992.
 157. Umeshita K , Monden M , Tono T , Hasuike Y , Kanai T , Gotoh M , Mori T , Shaked A , Busuttil RW . Determination of the presence of interleukin‐6 in bile after orthotopic liver transplantation. Its role in the diagnosis of acute rejection. Ann Surg 223: 204‐211, 1996.
 158. Uozumi N , Gao C , Yoshioka T , Nakano M , Moriwaki K , Nakagawa T , Masuda T , Tanabe M , Miyoshi E . Identification of a novel type of CA19‐9 carrier in human bile and sera of cancer patients: An implication of the involvement in nonsecretory exocytosis. J Proteome Res 9: 6345‐6353, 2010.
 159. Van Erpecum KJ . Pathogenesis of cholesterol and pigment gallstones: an update. Clin Res Hepatol Gastroenterol 35: 281‐287, 2011.
 160. Verkade HJ , Kuipers F , Domingo N , Havinga R , Leonardi J , Vonk RJ , Lafont H . Biliary secretion of anionic polypeptide fraction is not coupled to that of phospholipids and cholesterol in rats. Hepatology 25: 38‐47, 1997.
 161. Vogl T , Gharibyan AL , Morozova‐Roche LA . Pro‐inflammatory S100A8 and S100A9 proteins: Self‐assembly into multifunctional native and amyloid complexes. Int J Mol Sci 13: 2893‐2917, 2012.
 162. Waisberg J , Palma RT , Neto LC , Martins LC , Oliveira MS , Nagashima CA , Godoy AC , Goffi FS . Biliary carcinoembryonic antigen levels in diagnosis of occult hepatic metastases from colorectal carcinoma. World J Gastroenterol 9: 1589‐1593, 2003.
 163. Wang HH , Portincasa P , Wang DQ . Molecular pathophysiology and physical chemistry of cholesterol gallstones. Front Biosci 13: 401‐423, 2008.
 164. Wang W , Ai KX , Yuan Z , Huang XY , Zhang HZ . Different expression of S100A8 in malignant and benign gall bladder diseases. Dig Dis Sci 58: 150‐162, 2013.
 165. Weber A , von Weyhern C , Fend F , Schneider J , Neu B , Meining A , Weidenbach H , Schmid RM , Prinz C . Endoscopic transpapillary brush cytology and forceps biopsy in patients with hilar cholangiocarcinoma. World J Gastroenterol 14: 1097‐1101, 2008.
 166. West J , Wood H , Logan RF , Quinn M , Aithal GP . Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971‐2001. Br J Cancer 94: 1751‐1758, 2006.
 167. Wilkins MR. Proteome Research : New Frontiers in Functional Genomics. Berlin; New York: Springer, 1997.
 168. Wilkins MR , Pasquali C , Appel RD , Ou K , Golaz O , Sanchez JC , Yan JX , Gooley AA , Hughes G , Humphery‐Smith I , Williams KL , Hochstrasser DF . From proteins to proteomes: large scale protein identification by two‐dimensional electrophoresis and amino acid analysis. Biotechnology (N Y) 14: 61‐65, 1996.
 169. Yamazaki K , Powers SP , LaRusso NF . Biliary proteins: Assessment of quantitative techniques and comparison in gallstone and nongallstone subjects. J Lipid Res 29: 1055‐1063, 1988.
 170. Yang R , Miki K , Oksala N , Nakao A , Lindgren L , Killeen ME , Mennander A , Fink MP , Tenhunen J . Bile high‐mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia. Am J Physiol Regul Integr Comp Physiol 297: R362‐369, 2009.
 171. Yeatman TJ , Bland KI , Copeland EM, III , Hollenbeck JI , Souba WW , Vogel SB , Kimura AK . Relationship between colorectal liver metastases and CEA levels in gallbladder bile. Ann Surg 210: 505‐512, 1989.
 172. Yeh BM , Liu PS , Soto JA , Corvera CA , Hussain HK . MR imaging and CT of the biliary tract. Radiographics 29: 1669‐1688, 2009.
 173. Yue T , Goldstein IJ , Hollingsworth MA , Kaul K , Brand RE , Haab BB . The prevalence and nature of glycan alterations on specific proteins in pancreatic cancer patients revealed using antibody‐lectin sandwich arrays. Mol Cell Proteomics 8: 1697‐1707, 2009.
 174. Yue T , Partyka K , Maupin KA , Hurley M , Andrews P , Kaul K , Moser AJ , Zeh H , Brand RE , Haab BB . Identification of blood‐protein carriers of the CA 19‐9 antigen and characterization of prevalence in pancreatic diseases. Proteomics 11: 3665‐3674, 2011.
 175. Zabron AA , Horneffer‐van der Sluis VM , Wadsworth CA , Laird F , Gierula M , Thillainayagam AV , Vlavianos P , Westaby D , Taylor‐Robinson SD , Edwards RJ , Khan SA . Elevated levels of neutrophil gelatinase‐associated lipocalin in bile from patients with malignant pancreatobiliary disease. Am J Gastroenterol 106: 1711‐1717, 2011.
 176. Zhang B , Kirov S , Snoddy J . WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 33: W741‐748, 2005.
 177. Zhang D , Xiang J , Wang L , Xu Z , Sun L , Zhou F , Zha X , Cai D . Comparative proteomic analysis of gallbladder bile proteins related to cholesterol gallstones. PLoS One 8: e54489, 2013.
 178. Zhou H , Chen B , Li RX , Sheng QH , Li SJ , Zhang L , Li L , Xia QC , Wang HY , Zeng R . Large‐scale identification of human biliary proteins from a cholesterol stone patient using a proteomic approach. Rapid Commun Mass Spectrom 19: 3569‐3578, 2005.
 179. Zweers SJ , Booij KA , Komuta M , Roskams T , Gouma DJ , Jansen PL , Schaap FG . The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology 55: 575‐583, 2012.

Supplementary Information

Supplementary Table I: Comprehensive catalogue of gene products described to date in human bile by using proteomic approaches. Download (xlsx)

Supplementary Table II: List of bile proteins categorized in functional and biological classes. Download (pdf)

Supplementary Figure I: Characterization of the complete catalogue of bile proteins in terms of molecular functions. Highly enriched categories are shown in red. Download (bmp) Download (gif)

Supplementary Figure II: Characterization of the complete catalogue of bile proteins in terms of biological processes. Highly enriched categories are shown in red. Download (bmp) Download (gif)


Related Articles:

Bile Formation and Secretion
Overview of Bile Secretion
Pathways and Functions of Biliary Protein Secretion

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Annarita Farina, Myriam Delhaye, Pierre Lescuyer, Jean‐Marc Dumonceau. Bile Proteome in Health and Disease. Compr Physiol 2014, 4: 91-108. doi: 10.1002/cphy.c130016