KEGG   PATHWAY: ko04976Help
ko04976                     Pathway                                

Bile secretion
Bile is a vital secretion, essential for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Moreover, bile is an important route of elimination for excess cholesterol and many waste product, bilirubin, drugs and toxic compounds. Bile secretion depends on the function of membrane transport systems in hepatocytes and cholangiocytes and on the structural and functional integrity of the biliary tree. The hepatocytes generate the so-called primary bile in their canaliculi.  Cholangiocytes modify the canalicular bile by secretory and reabsorptive processes as bile passes through the bile ducts. The main solutes in bile are bile acids, which stimulate bile secretion osmotically, as well as facilitate the intestinal absorption of dietary lipids by their detergent properties. Bile acids are also important signalling molecules. Through the activation of nuclear receptors, they regulate their own synthesis and transport rates.
09150 Organismal Systems; 09154 Digestive system
BRITE hierarchy
Pathway map
ko04976  Bile secretion

Ortholog table
H00155  Familial hypercholesterolemia
H00208  Hyperbilirubinemia
H00624  Familial cholestasis
H00831  Primary dystonia
H00836  GLUT1 deficiency syndrome (GLUT1DS)
H00933  Hereditary pancreatitis
H01016  Primary bile acid malabsorption
H01213  Gallbladder disease
H01383  Hyperlipoproteinemia type IIa
H01935  Familial hypercholanemia
H02056  Dubin-Johnson syndrome
H02057  Rotor syndrome
Other DBs
BSID: 193095
GO: 0032782
K01253  microsomal epoxide hydrolase [EC:]
K03460  solute carrier organic anion transporter family, member 1A
K05043  solute carrier organic anion transporter family, member 1B
K14341  solute carrier family 10 (sodium/bile acid cotransporter), member 1
K08204  MFS transporter, OCT family, solute carrier family 22 (organic anion transporter), member 7
K08205  MFS transporter, OCT family, solute carrier family 22 (organic anion transporter), member 8
K08198  MFS transporter, OCT family, solute carrier family 22 (organic cation transporter), member 1
K00021  hydroxymethylglutaryl-CoA reductase (NADPH) [EC:]
K13885  scavenger receptor class B, member 1
K12473  low-density lipoprotein receptor
K14349  neutral cholesterol ester hydrolase 1 [EC:3.1.1.-]
K00489  cholesterol 7alpha-monooxygenase [EC:]
K08537  farnesoid X receptor
K08524  retinoid X receptor alpha
K08563  nuclear receptor subfamily 0 group B member 2
K11822  bile-salt sulfotransferase [EC:]
K08748  solute carrier family 27 (fatty acid transporter), member 5 [EC:]
K00659  bile acid-CoA:amino acid N-acyltransferase [EC:]
K09877  aquaporin-9
K09869  aquaporin-8
K05683  ATP-binding cassette, subfamily G (WHITE), member 5 (sterolin 1)
K05684  ATP-binding cassette, subfamily G (WHITE), member 8 (sterolin 2)
K05664  ATP-binding cassette, subfamily B (MDR/TAP), member 11
K05666  ATP-binding cassette, subfamily C (CFTR/MRP), member 2
K05681  ATP-binding cassette, subfamily G (WHITE), member 2
K18245  carbonic anhydrase 2 [EC:]
K13855  solute carrier family 4 (anion exchanger), member 2
K05658  ATP-binding cassette, subfamily B (MDR/TAP), member 1 [EC:]
K05659  ATP-binding cassette, subfamily B (MDR/TAP), member 4 [EC:]
K05742  solute carrier family 9 (sodium/hydrogen exchanger), member 1
K13857  solute carrier family 4 (sodium bicarbonate cotransporter), member 5
K05667  ATP-binding cassette, subfamily C (CFTR/MRP), member 3
K05673  ATP-binding cassette, subfamily C (CFTR/MRP), member 4
K14360  organic solute transporter subunit alpha
K14361  organic solute transporter subunit beta
K04943  potassium intermediate/small conductance calcium-activated channel subfamily N member 2
K01539  sodium/potassium-transporting ATPase subunit alpha [EC:]
K01540  sodium/potassium-transporting ATPase subunit beta
K01538  sodium/potassium-transporting ATPase subunit gamma (FXYD domain-containing ion transport regulator 2)
K04588  secretin receptor
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K08041  adenylate cyclase 1 [EC:]
K08042  adenylate cyclase 2 [EC:]
K08043  adenylate cyclase 3 [EC:]
K08044  adenylate cyclase 4 [EC:]
K08045  adenylate cyclase 5 [EC:]
K08046  adenylate cyclase 6 [EC:]
K08047  adenylate cyclase 7 [EC:]
K08048  adenylate cyclase 8 [EC:]
K08049  adenylate cyclase 9 [EC:]
K04345  protein kinase A [EC:]
K05031  cystic fibrosis transmembrane conductance regulator [EC:]
K13575  solute carrier family 4 (sodium bicarbonate cotransporter), member 4
K09866  aquaporin-4
K09864  aquaporin-1
K14342  solute carrier family 10 (sodium/bile acid cotransporter), member 2
K14158  solute carrier family 5 (sodium/glucose cotransporter), member 1
K12040  solute carrier family 9 (sodium/hydrogen exchanger), member 3
K07299  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1
C00001  H2O
C00011  CO2
C00024  Acetyl-CoA
C00026  2-Oxoglutarate
C00031  D-Glucose
C00051  Glutathione
C00080  H+
C00114  Choline
C00187  Cholesterol
C00238  Potassium cation
C00288  HCO3-
C00315  Spermidine
C00318  L-Carnitine
C00366  Urate
C00486  Bilirubin
C00504  Folate
C00575  3',5'-Cyclic AMP
C00584  Prostaglandin E2
C00639  Prostaglandin F2alpha
C00695  Cholic acid
C00698  Cl-
C00735  Cortisol
C00750  Spermine
C00780  Serotonin
C00805  Salicylate
C00865  Phospholipid
C00942  3',5'-Cyclic GMP
C01330  Sodium cation
C01353  Carbonic acid
C01405  Aspirin
C01443  Ouabain
C01576  Etoposide
C01829  Thyroxine
C01844  Pravastatin
C01921  Glycocholate
C01937  Methotrexate
C01996  Acetylcholine
C02165  Leukotriene B4
C02166  Leukotriene C4
C02380  6-Mercaptopurine
C02465  Triiodothyronine
C02528  Chenodeoxycholate
C02530  Cholesterol ester
C02538  Estrone 3-sulfate
C02918  1-Methylnicotinamide
C03033  beta-D-Glucuronoside
C03642  Taurolithocholate sulfate
C03758  Dopamine
C03990  Lithocholic acid
C04483  Deoxycholic acid
C04555  Dehydroepiandrosterone sulfate
C05122  Taurocholate
C05371  Microcystin LR
C05465  Taurochenodeoxycholate
C05466  Glycochenodeoxycholate
C05503  Estradiol-17beta 3-glucuronide
C05551  Penicillin G
C05963  Thromboxane B2
C06526  Quinine
C06570  Tetracycline
C06688  Rifampicin
C06804  Acetaminophen
C06810  Aciclovir
C06880  Cefazolin
C06890  Ceftizoxime
C06956  Digoxin
C06999  Fexofenadine
C07014  Fluvastatin
C07051  Indinavir
C07065  Lamivudine
C07151  Metformin
C07184  Valacyclovir
C07185  Valproic acid
C07201  Vinblastine
C07207  Zalcitabine
C07210  Zidovudine
C07240  Ritonavir
C07394  Paclitaxel
C07512  Tetraethylammonium
C07649  5-FU
C07660  Levofloxacin
C07966  Cerivastatin
C08357  Estradiol-17beta 3-sulfate
C08439  Phalloidin
C09955  Ochratoxin A
C11158  Topotecan
C11231  Docetaxel anhydrous
C11245  Glucuronosyletoposide
C11277  Adefovir
C11310  1-Methyl-4-phenylpyridinium
C11363  Sulfobromophthalein
C11587  BQ 123
C11754  Cephaloridine
C12560  Saquinavir mesylate
C13523  Secretin
C16114  Cholecystokinin-8
C16578  Morphine-6-glucuronide
C16643  Morphine-3-glucuronide
D00125  Etoposide (JP17/USP/INN)
D00140  Erythromycin (JP17/USP/INN)
D00142  Methotrexate (JP17/USP/INN)
D00184  Cyclosporine (USP)
D00186  Ciprofloxacin (JP17/USP/INN)
D00201  Tetracycline (JAN/USP/INN)
D00214  Dactinomycin (USP)
D00224  Allopurinol (JP17/USP/INN)
D00240  Aztreonam (JP17/USP/INN)
D00247  Bumetanide (JP17/USP/INN)
D00295  Cimetidine (JP17/USP/INN)
D00298  Digoxin (JP17/USP)
D00318  Famotidine (JP17/USP/INN)
D00331  Furosemide (JP17/USP/INN)
D00333  Ganciclovir (JAN/USP/INN)
D00340  Hydrochlorothiazide (JP17/USP/INN)
D00353  Lamivudine (JAN/USP/INN)
D00359  Lovastatin (USP/INN)
D00400  Valsartan (JP17/USAN/INN)
D00422  Ranitidine (USAN/INN)
D00427  Ritonavir (JAN/USAN/INN)
D00429  Saquinavir (JAN/USP/INN)
D00439  Nitrofurantoin (JAN/USP/INN)
D00453  Ofloxacin (JP17/USP/INN)
D00456  Ondansetron (JAN/USP/INN)
D00491  Paclitaxel (JAN/USP/INN)
D00512  Phenytoin (JP17/USP/INN)
D00521  Terfenadine (JAN/USAN/INN)
D00570  Colchicine (JP17/USP)
D00590  Sparfloxacin (JAN/USAN/INN)
D00767  Vecuronium bromide (JAN/USAN/INN)
D00804  Ivermectin (JAN/USAN/INN)
D01061  Irinotecan hydrochloride (USAN)
D01264  Daunorubicin hydrochloride (JP17/USP)
D01275  Doxorubicin hydrochloride (JP17/USP)
D01421  Aminohippurate sodium (USP)
D01745  Domperidone (JP17/USAN/INN)
D01862  Pitavastatin calcium (JAN)
D02115  Methotrexate sodium
D02166  Mitoxantrone hydrochloride (JAN/USP)
D02214  Epirubicin hydrochloride (JP17/USAN)
D02216  Ciprofloxacin hydrochloride (USP)
D02356  Verapamil (USAN/INN)
D03130  Bisantrene hydrochloride (USAN)
D03833  Indinavir (USAN)
D03899  Doxorubicin (USAN/INN)
D04931  Mercaptopurine (INN)
D05246  Olmesartan (USAN/INN)
D06050  Technetium Tc 99m tetrofosmin (USP)
D06074  Tenofovir (USAN)
D07448  Amitriptyline (INN)
D07538  Bosentan (INN)
D07626  Caspofungin (INN)
D07661  Cerivastatin (INN)
D07776  Daunorubicin (INN)
D07845  Diltiazem (INN)
D07866  Docetaxel (JAN/INN)
D07901  Epirubicin (INN)
D07907  Erlotinib (INN)
D07958  Fexofenadine (INN)
D07986  Folinic acid (BAN)
D07987  Folinic acid calcium salt pentahydrate
D08066  Imatinib (INN)
D08086  Irinotecan (INN)
D08108  Lapatinib (INN)
D08144  Loperamide (INN)
D08146  Losartan (INN)
D08224  Mitoxantrone (INN)
D08259  Nelfinavir (INN)
D08291  Ofloxacin hydrochloride
D08306  Oseltamivir (INN)
D08411  Prazosin (INN)
D08458  Quinidine (BAN)
D08492  Rosuvastatin (INN)
D08618  Topotecan (BAN)
D08675  Vinblastine (INN)
D08679  Vincristine (INN)
Meier PJ, Stieger B
Bile salt transporters.
Annu Rev Physiol 64:635-61 (2002)
Kullak-Ublick GA, Beuers U, Paumgartner G
Hepatobiliary transport.
J Hepatol 32:3-18 (2000)
Kosters A, Karpen SJ
Bile acid transporters in health and disease.
Xenobiotica 38:1043-71 (2008)
Anwer MS
Cellular regulation of hepatic bile acid transport in health and cholestasis.
Hepatology 39:581-90 (2004)
Alrefai WA, Gill RK
Bile acid transporters: structure, function, regulation and pathophysiological implications.
Pharm Res 24:1803-23 (2007)
Trauner M, Boyer JL
Bile salt transporters: molecular characterization, function, and regulation.
Physiol Rev 83:633-71 (2003)
Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev 62:1-96 (2010)
Trauner M, Wagner M, Fickert P, Zollner G
Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis.
J Clin Gastroenterol 39:S111-24 (2005)
Arrese M, Trauner M
Molecular aspects of bile formation and cholestasis.
Trends Mol Med 9:558-64 (2003)
Esteller A
Physiology of bile secretion.
World J Gastroenterol 14:5641-9 (2008)
Takikawa H
Hepatobiliary transport of bile acids and organic anions.
J Hepatobiliary Pancreat Surg 9:443-7 (2002)
St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, Meier PJ
Transport of bile acids in hepatic and non-hepatic tissues.
J Exp Biol 204:1673-86 (2001)
Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K
Targeting bile-acid signalling for metabolic diseases.
Nat Rev Drug Discov 7:678-93 (2008)
Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ
Enterohepatic transport of bile salts and genetics of cholestasis.
J Hepatol 43:342-57 (2005)
Pellicoro A, Faber KN
Review article: The function and regulation of proteins involved in bile salt biosynthesis and transport.
Aliment Pharmacol Ther 26 Suppl 2:149-60 (2007)
Jonker JW, Stedman CA, Liddle C, Downes M
Hepatobiliary ABC transporters: physiology, regulation and implications for disease.
Front Biosci 14:4904-20 (2009)
Modica S, Bellafante E, Moschetta A
Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio.
Front Biosci 14:4719-45 (2009)
Cai SY, Boyer JL
FXR: a target for cholestatic syndromes?
Expert Opin Ther Targets 10:409-21 (2006)
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 14:2829-44 (2009)
Roma MG, Crocenzi FA, Sanchez Pozzi EA
Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects.
Clin Sci (Lond) 114:567-88 (2008)
Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ
Molecular pathogenesis of intrahepatic cholestasis of pregnancy.
Expert Rev Mol Med 10:e9 (2008)
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