Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. Individual bile acid carriers have now been cloned from several species. Na(+)-dependent transporters that mediate uptake into hepatocytes and reabsorption from the intestine and biliary epithelium and an ATP-dependent transporter that pumps bile acids into bile comprise the classes of transporter that are specific for bile acids. In addition, at least four human and five rat genes that code for Na(+)-independent organic anion carriers with broad multi-substrate specificities that include bile acids have been discovered. Studies concerning the regulation of these carriers have permitted identification of molecular signals that dictate eventual changes in the uptake or excretion of bile acids, which in turn have profound physiological implications. This overview summarizes and compares all known bile acid transporters and highlights findings that have identified diseases linked to molecular defects in these carriers. Recent advances that have fostered a more complete appreciation for the elaborate disposition of bile acids in humans are emphasized.

REFERENCES

Abe
T.
,
Kakyo
M.
,
Tokui
T.
,
Nakagomi
R.
,
Nishio
T.
,
Nakai
D.
,
Nomura
H.
,
Unno
M.
,
Suzuki
M.
,
Naitoh
T.
,
Matsuno
S.
,
Yawo
H.
(
1999
).
Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1.
J. Biol. Chem
274
,
17159
–.
Aldini
R.
,
Roda
A.
,
Labate
A. M.
,
Cappelleri
G.
,
Roda
E.
,
Barbara
L.
(
1982
).
Hepatic bile acid uptake: effect of conjugation, hydroxyl and keto groups and albumin binding.
J. Lipid Res
23
,
1167
–.
Alpini
G.
,
Glaser
S.
,
Robertson
W.
,
Phinizy
J. L.
,
Rodgers
R. E.
,
Caligiuri
A.
,
LeSage
G.
(
1997
).
Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes.
Am. J. Physiol
273
,
518
–.
Alpini
G.
,
Glaser
S. S.
,
Rodgers
R.
,
Phinizy
J. L.
,
Robertson
W. E.
,
Lasater
J.
,
Caligiuri
A.
,
Tretjak
Z.
,
LeSage
G. D.
(
1997
).
Functional expression of the apical Na+-dependent bile acid transporter in large but not small rat cholangiocytes.
Gastroenterology
113
,
1734
–.
Alpini
G.
,
Glaser
S. S.
,
Ueno
Y.
,
Rodgers
R.
,
Phinizy
J. L.
,
Francis
H.
,
Baiocchi
L.
,
Holcomb
L. A.
,
Caligiuri
A.
,
LeSage
G. D.
(
1999
).
Bile acid feeding induces cholangiocyte proliferation and secretion: evidence for bile acid-regulated ductal secretion.
Gastroenterology
116
,
179
–.
Amelsberg
A.
,
Jochims
C.
,
Richter
C. P.
,
Nitsche
R.
,
Folsch
U. R.
(
1999
).
Evidence for an anion exchange mechanism for uptake of conjugated bile acid from the rat jejunum.
Am. J. Physiol
276
,
737
–.
Angeletti
R. H.
,
Novikoff
P. M.
,
Juvvadi
S. R.
,
Fritschy
J. M.
,
Meier
P. J.
,
Wolkoff
A. W.
(
1997
).
The choroid plexus epithelium is the site of the organic anion transport protein in the brain.
Proc. Natl. Acad. Sci. USA
94
,
283
–.
Arrese
M.
,
Trauner
M.
,
Sacchiero
R. J.
,
Crossman
M. W.
,
Shneider
B. L.
(
1998
).
Neither intestinal sequestration of bile acids nor common bile duct ligation modulate the expression and function of the rat ileal bile acid transporter.
Hepatology
28
,
1081
–.
Balistreri
W. F.
(
1999
).
Inborn errors of bile acid biosynthesis and transport. Novel forms of metabolic liver disease. Gastroenterol.
Clin. North Am
28
,
145
–.
Benedetti
A.
,
Di Sario
A.
,
Marucci
L.
,
Svegliati-Baroni
G.
,
Schteingart
C. D.
,
Ton-Nu
H. T.
,
Hofmann
A. F.
(
1997
).
Carrier-mediated transport of conjugated bile acids across the basolateral membrane of biliary epithelial cells.
Am. J. Physiol
272
,
1416
–.
Bergwerk
A. J.
,
Shi
X.
,
Ford
A. C.
,
Kanai
N.
,
Jacquemin
E.
,
Burk
R. D.
,
Bai
S.
,
Novikoff
P. M.
,
Stieger
B.
,
Meier
P. J.
,
Schuster
V. L.
,
Wolkoff
A. W.
(
1996
).
Immunologic distribution of an organic anion transport protein in rat liver and kidney.
Am. J. Physiol
271
,
231
–.
Bjorkhem
I.
,
Andersson
O.
,
Diczfalusy
U.
,
Sevastik
B.
,
Xiu
R. J.
,
Duan
C.
,
Lund
E.
(
1994
).
Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages.
Proc. Natl. Acad. Sci. USA
91
,
8592
–.
Bolder
U.
,
Ton-Nu
H. T.
,
Schteingart
C. D.
,
Frick
E.
,
Hofmann
A. F.
(
1997
).
Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion.
Gastroenterology
112
,
214
–.
Bossard
R.
,
Stieger
B. B. O. N.
,
Fricker
G.
,
Meier
P. J.
(
1993
).
Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver.
J. Clin. Invest
91
,
2714
–.
Bossuyt
X.
,
Muller
M.
,
Hagenbuch
B.
,
Meier
P. J.
(
1996
).
Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver.
J. Pharmac. Exp. Ther
276
,
891
–.
Boyer
J. L.
,
Soroka
C. J.
(
1995
).
Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets.
Gastroenterology
109
,
1600
–.
Bravo
P.
,
Marin
J. J.
,
Beveridge
M. J.
,
Novak
D. A.
(
1995
).
Reconstitution and characterization of ATP-dependent bile acid transport in human and rat placenta.
Biochem. J
311
,
479
–.
Buscher
H. P.
,
Meder
I.
,
MacNelly
S.
,
Gerok
W.
(
1993
).
Zonal changes of hepatobiliary taurocholate transport in intra-hepatic cholestasis induced by 17 alpha-ethinyl estradiol: a histoautoradiographic study in rats.
Hepatology
17
,
494
–.
Cali
J. J.
,
Hsieh
C. L.
,
Francke
U.
,
Russell
D. W.
(
1991
).
Mutationsin the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.
J. Biol. Chem
266
,
7779
–.
Cali
J. J.
,
Russell
D. W.
(
1991
).
Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis.
J. Biol. Chem
266
,
7774
–.
Cattori
V.
,
Eckhardt
U.
,
Hagenbuch
B.
(
1999
).
Molecular cloning and functional characterization of two alternatively spliced Ntcp isoforms from mouse liver.
Biochim. Biophys. Acta
1445
,
154
–.
Cattori
V.
,
Hagenbuch
B.
,
Hagenbuch
N.
,
Stieger
B.
,
Winterhalter
K. E.
,
Meier
P. J.
(
2000
).
Identification of a novel rat organic anion transporting polypeptide (Oatp4) as a full-length isoform of the liver-specific transporter-1 (rlst-1).
FEBS Lett
474
,
242
–.
Cattori
V.
,
Hagenbuch
B.
,
Stieger
B.
,
Landmann
L.
,
Winterhalter
K. H.
,
Meier
P. J.
(
2000
).
Characterization of the rat liver organic anion transporting polypeptide 4 (Oatp4) and its comparison with Oatp3.
Hepatology
32
,
437
–.
Childs
S.
,
Yeh
R. L.
,
Georges
E.
,
Ling
V.
(
1995
).
Identification of a sister gene to P-glycoprotein.
Cancer Res
55
,
2029
–.
Childs
S.
,
Yeh
R. L.
,
Hui
D.
,
Ling
V.
(
1998
).
Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein.
Cancer Res
58
,
4160
–.
Christie
D. M.
,
Dawson
P. A.
,
Thevananther
S.
,
Shneider
B. L.
(
1996
).
Comparative analysis of the ontogeny of a sodium-dependent bileacid transporter in rat kidney and ileum.
Am. J. Physiol
271
,
377
–.
Cole
S. P.
,
Bhardwaj
G.
,
Gerlach
J. H.
,
Mackie
J. E.
,
Grant
C. E.
,
Almquist
K. C.
,
Stewart
A. J.
,
Kurz
E. U.
,
Duncan
A. M.
,
Deeley
R. G.
(
1992
).
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.
Science
258
,
1650
–.
Cowen
A. E.
,
Korman
M. G.
,
Hofmann
A. F.
,
Cass
O. W.
(
1975
).
Metabolism of lethocholate in healthy man. I. Biotransformation and biliary excretion of intravenously administered lithocholate, lithocholylglycine and their sulfates.
Gastroenterology
69
,
59
–.
Craddock
A. L.
,
Love
M. W.
,
Daniel
R. W.
,
Kirby
L. C.
,
Walters
H. C.
,
Wong
M. H.
,
Dawson
P. A.
(
1998
).
Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter.
Am. J. Physiol
274
,
157
–.
Cui
Y.
,
König
J.
,
Buchholz
U.
,
Spring
H.
,
Leier
I.
,
Keppler
D.
(
1999
).
Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells.
Mol. Pharmac
55
,
929
–.
Dawson
P. A.
,
Oelkers
P.
(
1995
).
Bile acid transporters.
Curr. Opin. Lipidol
6
,
109
–.
Denson
L. A.
,
Auld
K. L.
,
Schiek
D. S.
,
McClure
M. H.
,
Mangelsdorf
D. J.
,
Karpen
S. J.
(
2000
).
Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation.
J. Biol. Chem
275
,
8835
–.
Dray-Charier
N.
,
Paul
A.
,
Combettes
L.
,
Bouin
M.
,
Mergey
M.
,
Balladur
P.
,
Capeau
J.
,
Housset
C.
(
1997
).
Regulation of mucin secretion in human gallbladder epithelial cells: predominant role of calcium and protein kinase C.
Gastroenterology
112
,
978
–.
Duane
W. C.
(
1993
).
Effects of lovastatin and dietary cholesterol on sterol homeostasis in healthy human subjects.
J. Clin. Invest
92
,
911
–.
Eckhardt
U.
,
Schroeder
A.
,
Stieger
B.
,
Höchli
M.
,
Landmann
L.
,
Tynes
R.
,
Meier
P. J.
,
Hagenbuch
B.
(
1999
).
Polyspecific substrate uptake by the hepatic organic anion transporter oatp1 in stably transfected CHO cells.
Am. J. Physiol
276
,
1037
–.
Evers
R.
,
Kool
M.
,
van Deemter
L.
,
Janssen
H.
,
Calafat
J.
,
Oomen
L. C.
,
Paulusma
C. C.
,
Oude Elferink
R. P.
,
Baas
F.
,
Schinkel
A. H.
,
Borst
P.
(
1998
).
Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA.
J. Clin. Invest
101
,
1310
–.
Falany
C. N.
,
Johnson
M. R.
,
Barnes
S.
,
Diasio
R. B.
(
1994
).
Glycine and taurine conjugation of bile acids by a single enzyme. Molecular cloning and expression of human liver bile acid CoA:amino acid N-acyltransferase.
J. Biol. Chem
269
,
19375
–.
Ganguly
T. C.
,
O'Brien
M. L.
,
Karpen
S. J.
,
Hyde
J. F.
,
Suchy
F. J.
,
Vore
M.
(
1997
).
Regulation of the rat liver sodium-dependent bile acid cotransporter gene by prolactin — Mediation of transcriptional activation by Stat5.
J. Clin. Invest
99
,
2906
–.
Meier
P. J.
(
2000
).
Organic anion transporting polypeptides mediate transport of opioid peptides across the blood—brain barrier.
J. Pharmac. Exp. Ther
294
,
73
–.
Gao
B.
,
Stieger
B.
,
Noe
B.
,
Fritschy
J. M.
,
Meier
P. J.
(
1999
).
Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain.
J. Histochem. Cytochem
47
,
1255
–.
Gartung
C.
,
Ananthanarayanan
M.
,
Rahman
M. A.
,
Schuele
S.
,
Nundy
S.
,
Soroka
C. J.
,
Stolz
A.
,
Suchy
F. J.
,
Boyer
J. L.
(
1996
).
Downregulation of expression and function of the rat liver Na+/bile acid cotransporter in extra-hepatic cholestasis.
Gastroenterology
110
,
199
–.
Gerloff
T.
,
Stieger
B.
,
Hagenbuch
B.
,
Madon
J.
,
Landmann
L.
,
Roth
J.
,
Hofmann
A. F.
,
Meier
P. J.
(
1998
).
The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.
J. Biol. Chem
273
,
10046
–.
Green
R. M.
,
Beier
D.
,
Gollan
J. L.
(
1996
).
Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents.
Gastroenterology
111
,
193
–.
Green
R. M.
,
Hoda
F.
,
Ward
K. L.
(
2000
).
Molecular cloning and characterization of the murine bile salt export pump.
Gene
241
,
117
–.
Groothuis
G. M.
,
Hardonk
M. J.
,
Keulemans
K. P.
,
Nieuwenhuis
P.
,
Meijer
D. K.
(
1982
).
Autoradiographic and kinetic demonstration of acinar heterogeneity of taurocholate transport.
Am. J. Physiol
243
,
455
–.
Gurantz
D.
,
Schteingart
C. D.
,
Hagey
L. R.
,
Steinbach
J. H.
,
Grotmol
T.
,
Hofmann
A. F.
(
1991
).
Hypercholeresis induced by unconjugated bile acid infusion correlates with recovery in bile of unconjugated bile acids.
Hepatology
13
,
540
–.
Hagenbuch
B.
,
Meier
P. J.
(
1994
).
Molecular cloning, chromosomal localization and functional characterization of a human liver Na+/bile acid cotransporter.
J. Clin. Invest
93
,
1326
–.
Hagenbuch
B.
,
Stieger
B.
,
Foguet
M.
,
Lubbert
H.
,
Meier
P. J.
(
1991
).
Functional expression cloning and characterization of the hepatocyte Na+/bile acid cotransport system.
Proc. Natl. Acad. Sci. USA
88
,
10629
–.
Hallen
S.
,
Branden
M.
,
Dawson
P. A.
,
Sachs
G.
(
1999
).
Membrane insertion scanning of the human ileal sodium/bile acid co-transporter.
Biochemistry
38
,
11379
–.
Hatanaka
H.
,
Kawaguchi
A.
,
Hayakawa
S.
,
Katsuki
H.
(
1972
).
Structural specificity of bile acid for inhibition of sterol synthesis in cell-free extracts of yeast.
Biochim. Biophys. Acta
270
,
397
–.
Higgins
C. F.
(
1995
).
The ABC of channel regulation.
Cell
82
,
693
–.
Hirohashi
T.
,
Suzuki
H.
,
Chu
X. Y.
,
Tamai
I.
,
Tsuji
A.
,
Sugiyama
Y.
(
2000
).
Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2).
J. Pharmac. Exp. Ther
292
,
265
–.
Hirohashi
T.
,
Suzuki
H.
,
Takikawa
H.
,
Sugiyama
Y.
(
2000
).
ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3).
J. Biol. Chem
275
,
2905
–.
Hofmann
A. F.
(
1999
).
Regulation of ileal bile acid transport: desirability of measuring transport function as well as transporter activity.
Hepatology
29
,
1335
–.
Hsiang
B.
,
Zhu
Y.
,
Wang
Z.
,
Wu
Y.
,
Sasseville
V.
,
Yang
W. P.
,
Kirchgessner
T. G.
(
1999
).
A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters.
J. Biol. Chem
274
,
37161
–.
Jacquemin
E.
(
1999
).
Progressive familial intra-hepatic cholestasis.
J. Gastroenterol. Hepatol
14
,
594
–.
Jacquemin
E.
,
Hagenbuch
B.
,
Stieger
B.
,
Wolkoff
A. W.
,
Meier
P. J.
(
1994
).
Expression cloning of a rat liver Na+-independent organic anion transporter.
Proc. Natl. Acad. Sci. USA
91
,
133
–.
Jansen
P. L.
,
Strautnieks
S. S.
,
Jacquemin
E.
,
Hadchouel
M.
,
Sokal
E. M.
,
Hooiveld
G. J.
,
Koning
J. H.
,
De Jager-Krikken
A.
,
Kuipers
F.
,
Stellaard
F.
,
Bijleveld
C. M.
,
Gouw
A.
,
Van Goor
H.
,
Thompson
R. J.
,
Muller
M.
(
1999
).
Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intra-hepatic cholestasis.
Gastroenterology
117
,
1370
–.
Jelinek
D. F.
,
Andersson
S.
,
Slaughter
C. A.
,
Russell
D. W.
(
1990
).
Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.
J. Biol. Chem
265
,
8190
–.
Jones
B. A.
,
Rao
Y. P.
,
Stravitz
R. T.
,
Gores
G. J.
(
1997
).
Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C.
Am. J. Physiol
272
,
1109
–.
Kakyo
M.
,
Sakagami
H.
,
Nishio
T.
,
Nakai
D.
,
Nakagomi
R.
,
Tokui
T.
,
Naitoh
T.
,
Matsuno
S.
,
Abe
T.
,
Yawo
H.
(
1999
).
Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2).
FEBS Lett
445
,
343
–.
Karpen
S. J.
,
Sun
A. Q.
,
Kudish
B.
,
Hagenbuch
B.
,
Meier
P. J.
,
Ananthanarayanan
M.
,
Suchy
F. J.
(
1996
).
Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter.
J. Biol. Chem
271
,
15211
–.
Kawaguchi
A.
(
1970
).
Control of ergosterol biosynthesis in yeast. Existence of lipid inhibitors.
J. Biochem
67
,
219
–.
Keppler
D.
,
Leier
I.
,
Jedlitschky
G.
(
1997
).
Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2.
Biol. Chem
378
,
787
–.
Kiuchi
Y.
,
Suzuki
H.
,
Hirohashi
T.
,
Tyson
C. A.
,
Sugiyama
Y.
(
1998
).
cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (Mrp3).
FEBS Lett
433
,
149
–.
Konig
J.
,
Cui
Y.
,
Nies
A. T.
,
Keppler
D.
(
2000
).
Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide.
J. Biol. Chem
275
,
23161
–.
Konig
J.
,
Cui
Y.
,
Nies
A. T.
,
Keppler
D.
(
2000
).
A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane.
Am. J. Physiol
278
,
156
–.
Konig
J.
,
Nies
A. T.
,
Cui
Y.
,
Leier
I.
,
Keppler
D.
(
1999
).
Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity and MRP2-mediated drug resistance.
Biochim. Biophys. Acta
1461
,
377
–.
Konig
J.
,
Rost
D.
,
Cui
Y.
,
Keppler
D.
(
1999
).
Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane.
Hepatology
29
,
1156
–.
Kool
M.
,
de Haas
M.
,
Scheffer
G. L.
,
Scheper
R. J.
,
van Eijk
M. J.
,
Juijn
J. A.
,
Baas
F.
,
Borst
P.
(
1997
).
Analysis of expression of cMOAT (MRP2), MRP3, MRP4 and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines.
Cancer Res
57
,
3537
–.
Kool
M.
,
van der Linden
M.
,
de Haas
M.
,
Scheffer
G. L.
,
de Vree
J. M.
,
Smith
A. J.
,
Jansen
G.
,
Peters
G. J.
,
Ponne
N.
,
Scheper
R. J.
,
Elferink
R. P.
,
Baas
F.
,
Borst
P.
(
1999
).
MRP3, an organic anion transporter able to transport anti-cancer drugs.
Proc. Natl. Acad. Sci. USA
96
,
6914
–.
Koop
I.
,
Schindler
M.
,
Bosshammer
A.
,
Scheibner
J.
,
Stange
E.
,
Koop
H.
(
1996
).
Physiological control of cholecystokinin release and pancreatic enzyme secretion by intraduodenal bile acids.
Gut
39
,
661
–.
Kullak-Ublick
G. A.
,
Fisch
T.
,
Oswald
M.
,
Hagenbuch
B.
,
Meier
P. J.
,
Beuers
U.
,
Paumgartner
G.
(
1998
).
Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain.
FEBS Lett
424
,
173
–.
Kullak-Ublick
G. A.
,
Hagenbuch
B.
,
Stieger
B.
,
Schteingart
C. D.
,
Hofmann
A. F.
,
Wolkoff
A. W.
,
Meier
P. J.
(
1995
).
Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver.
Gastroenterology
109
,
1274
–.
Kullak-Ublick
G. A.
,
Ismair
M. G.
,
Stieger
B.
,
Landmann
L.
,
Huber
R.
,
Pizzagalli
F.
,
Fattinger
K.
,
Meier
P. J.
,
Hagenbuch
B.
(
2001
).
Organic anion transporting polypeptide B (OATP-B) and its functional comparison with three other OATPS of human liver.
Gastroenterology
120
,
525
–.
Kupferschmidt
H.
,
Hagenbuch
B.
,
Stieger
B.
,
Kraehenbuhl
S.
,
Meier
P. J.
(
1994
).
Ethinylestradiol induces differential effects on various transporter mRNA and protein levels in rat liver.
Hepatology
20
,
175
–.
Lazaridis
K. N.
,
Pham
L.
,
Tietz
P.
,
Marinelli
R. A.
,
deGroen
P. C.
,
Levine
S.
,
Dawson
P. A.
,
LaRusso
N. F.
(
1997
).
Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter.
J. Clin. Invest
100
,
2714
–.
Lazaridis
K. N.
,
Tietz
P.
,
Wu
T.
,
Kip
S.
,
Dawson
P. A.
,
LaRusso
N. F.
(
2000
).
Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties.
Proc. Natl. Acad. Sci. USA
97
,
11092
–.
Lee
J. M.
,
Trauner
M.
,
Soroka
C. J.
,
Stieger
B.
,
Meier
P. J.
,
Boyer
J. L.
(
2000
).
Expression of the bile salt export pump is maintained after chronic cholestasis in the rat.
Gastroenterology
118
,
163
–.
Li
L.
,
Lee
T. K.
,
Meier
P. J.
,
Ballatori
N.
(
1998
).
Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter.
J. Biol. Chem
273
,
16184
–.
Li
L.
,
Meier
P. J.
,
Ballatori
N.
(
2000
).
Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione.
Mol. Pharmac
58
,
335
–.
Lillienau
J.
,
Crombie
D. L.
,
Munoz
J.
,
Longmire-Cook
S. J.
,
Hagey
L. R.
,
Hofmann
A. F.
(
1993
).
Negative feedback regulation of the ileal bile acid transport system in rodents.
Gastroenterology
104
,
38
–.
Lu
T. T.
,
Makishima
M.
,
Repa
J. J.
,
Schoonjans
K.
,
Kerr
T. A.
,
Auwerx
J.
,
Mangelsdorf
D. J.
(
2000
).
Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.
Mol. Cell
6
,
507
–.
Lund
E.
,
Andersson
O.
,
Zhang
J.
,
Babiker
A.
,
Ahlborg
G.
,
Diczfalusy
U.
,
Einarsson
K.
,
Sjövall
J.
,
Björkhem
I.
(
1996
).
Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans.
Arterioscler. Thromb. Vasc. Biol
16
,
208
–.
Makishima
M.
,
Okamoto
A. Y.
,
Repa
J. J.
,
Tu
H.
,
Learned
R. M.
,
Luk
A.
,
Hull
M. V.
,
Lustig
K. D.
,
Mangelsdorf
D. J.
,
Shan
B.
(
1999
).
Identification of a nuclear receptor for bile acids.
Science
284
,
1362
–.
Marin
J. J.
,
Serrano
M. A.
,
el-Mir
M. Y.
,
Eleno
N.
,
Boyd
C. A.
(
1990
).
Bile acid transport by basal membrane vesicles of human term placental trophoblast.
Gastroenterology
99
,
1431
–.
Martin
K. O.
,
Budai
K.
,
Javitt
N. B.
(
1993
).
Cholesterol and 27-hydroxycholesterol 7 alpha-hydroxylation: evidence for two different enzymes.
J. Lipid Res
34
,
581
–.
Masuda
S.
,
Ibaramoto
K.
,
Takeuchi
A.
,
Saito
H.
,
Hashimoto
Y.
,
Inui
K. I.
(
1999
).
Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney.
Mol. Pharmac
55
,
743
–.
Masuda
S.
,
Saito
H.
,
Nonoguchi
H.
,
Tomita
K.
,
Inui
K.
(
1997
).
mRNA distribution and membrane localization of the Oat-K1 organic anion transporter in rat renal tubules.
FEBS Lett
407
,
127
–.
Mayer
R.
,
Kartenbeck
J.
,
Buchler
M.
,
Jedlitschky
G.
,
Leier
I.
,
Keppler
D.
(
1995
).
Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes.
J. Cell Biol
131
,
137
–.
Mekhjian
H. S.
,
Phillips
S. F.
,
Hofmann
A. F.
(
1979
).
Colonic absorption of unconjugated bile acids: perfusion studies in man.
Dig. Dis. Sci
24
,
545
–.
Misra
S.
,
Ujhazy
P.
,
Gatmaitan
Z.
,
Varticovski
L.
,
Arias
I. M.
(
1998
).
The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver.
J. Biol. Chem
273
,
26638
–.
Misra
S.
,
Ujhazy
P.
,
Varticovski
L.
,
Arias
I. M.
(
1999
).
Phosphoinositide 3-kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles.
Proc. Natl. Acad. Sci. USA
96
,
5814
–.
Moyer
M. S.
,
Heubi
J. E.
,
Goodrich
A. L.
,
Balistreri
W. F.
,
Suchy
F. J.
(
1986
).
Ontogeny of bile acid transport in brush border membrane vesicles from rat ileum.
Gastroenterology
90
,
1188
–.
Nakagawa
M.
,
Setchell
K. D.
(
1990
).
Bile acid metabolism in early life: studies of amniotic fluid.
J. Lipid Res
31
,
1089
–.
Nguyen
L. B.
,
Xu
G.
,
Shefer
S.
,
Tint
G. S.
,
Batta
A.
,
Salen
G.
(
1999
).
Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol 7alpha-hydroxylase activities in the rat, guinea pig and rabbit: effects of cholesterol and bile acids.
Metabolism
48
,
1542
–.
Nishida
T.
,
Gatmaitan
Z.
,
Che
M.
,
Arias
I. M.
(
1991
).
Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system.
Proc. Natl. Acad. Sci. USA
88
,
6590
–.
Nittono
H.
,
Obinata
K.
,
Nakatsu
N.
,
Watanabe
T.
,
Niijima
S.
,
Sasaki
H.
,
Arisaka
O.
,
Kato
H.
,
Yabuta
K.
,
Miyano
T.
(
1986
).
Sulfated and nonsulfated bile acids in urine of patients with biliary atresia: analysis of bile acids by high-performance liquid chromatography.
J. Pediatr. Gastroenterol. Nutr
5
,
23
–.
Noe
B.
,
Hagenbuch
B.
,
Stieger
B.
,
Meier
P. J.
(
1997
).
Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain.
Proc. Natl. Acad. Sci. USA
94
,
10346
–.
Oelkers
P.
,
Kirby
L. C.
,
Heubi
J. E.
,
Dawson
P. A.
(
1997
).
Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2).
J. Clin. Invest
99
,
1880
–.
Ogawa
K.
,
Suzuki
H.
,
Hirohashi
T.
,
Ishikawa
T.
,
Meier
P. J.
,
Hirose
K.
,
Akizawa
T.
,
Yoshioka
M.
,
Sugiyama
Y.
(
2000
).
Characterization of inducible nature of MRP3 in rat liver.
Am. J. Physiol
278
,
438
–.
Ortiz
D. F.
,
St-Pierre
M. V.
,
Abdulmessih
A.
,
Arias
I. M.
(
1997
).
A yeast ATP-binding cassette-type protein mediating ATP-dependent bile acid transport.
J. Biol. Chem
272
,
15358
–.
Pandak
W. M.
,
Li
Y. C.
,
Chiang
J. Y.
,
Studer
E. J.
,
Gurley
E. C.
,
Heuman
D. M.
,
Vlahcevic
Z. R.
,
Hylemon
P. B.
(
1991
).
Regulation of cholesterol 7 alpha-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat.
J. Biol. Chem
266
,
3416
–.
Parks
D. J.
,
Blanchard
S. G.
,
Bledsoe
R. K.
,
Chandra
G.
,
Consler
T. G.
,
Kliewer
S. A.
,
Stimmel
J. B.
,
Willson
T. M.
,
Zavacki
A. M.
,
Moore
D. D.
,
Lehmann
J. M.
(
1999
).
Bile acids: natural ligands for an orphan nuclear receptor.
Science
284
,
1365
–.
Paulusma
C. C.
,
Bosma
P. J.
,
Zaman
G. J. R.
,
Bakker
C. T. M.
,
Otter
M.
,
Scheffer
G. L.
,
Scheper
R. J.
,
Borst
P.
,
Oude Elferink
R. P. J.
(
1996
).
Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene.
Science
271
,
1126
–.
Paulusma
C. C.
,
Kool
M.
,
Bosma
P. J.
,
Scheffer
G. L.
,
ter Borg
F.
,
Scheper
R. J.
,
Tytgat
G. N.
,
Borst
P.
,
Baas
F.
,
Oude Elferink
R. P.
(
1997
).
A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin—Johnson syndrome.
Hepatology
25
,
1539
–.
Peet
D. J.
,
Turley
S. D.
,
Ma
W.
,
Janowski
B. A.
,
Lobaccaro
J. M.
,
Hammer
R. E.
,
Mangelsdorf
D. J.
(
1998
).
Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha.
Cell
93
,
693
–.
Pikuleva
I. A.
,
Bjorkhem
I.
,
Waterman
M. R.
(
1997
).
Expression, purification and enzymatic properties of recombinant human cytochrome P450c27 (CYP27).
Arch. Biochem. Biophys
343
,
123
–.
Que
F. G.
,
Phan
V. A.
,
Phan
V. H.
,
LaRusso
N. F.
,
Gores
G. J.
(
1999
).
GUDC inhibits cytochrome c release from human cholangiocyte mitochondria.
J. Surg. Res
83
,
100
–.
Raedsch
R.
,
Lauterburg
B. H.
,
Hofmann
A. F.
(
1981
).
Altered bile acid metabolism in primary biliary cirrhosis.
Dig. Dis. Sci
26
,
394
–.
Rao
Y. P.
,
Vlahcevic
Z. R.
,
Stravitz
R. T.
,
Mallonee
D. H.
,
Mullick
J.
,
Avadhani
N. G.
,
Hylemon
P. B.
(
1999
).
Downregulation of the rat hepatic sterol 27-hydroxylase gene by bile acids in transfected primary hepatocytes: possible role of hepatic nuclear factor 1alpha.
J. Steroid Biochem. Mol. Biol
70
,
1
–.
Reichel
C.
,
Gao
B.
,
Van Montfoort
J.
,
Cattori
V.
,
Rahner
C.
,
Hagenbuch
B.
,
Stieger
B.
,
Kamisako
T.
,
Meier
P. J.
(
1999
).
Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver.
Gastroenterology
117
,
688
–.
Reiss
A. B.
,
Martin
K. O.
,
Rojer
D. E.
,
Iyer
S.
,
Grossi
E. A.
,
Galloway
A. C.
,
Javitt
N. B.
(
1997
).
Sterol 27-hydroxylase: expression in human arterial endothelium.
J. Lipid Res
38
,
1254
–.
Roelofsen
H.
,
Vos
T. A.
,
Schippers
I. J.
,
Kuipers
F.
,
Koning
H.
,
Moshage
H.
,
Jansen
P. L.
,
Muller
M.
(
1997
).
Increased levels of the multidrug resistance protein in lateral membranes of proliferating hepatocyte-derived cells.
Gastroenterology
112
,
511
–.
Satlin
L. M.
,
Amin
V.
,
Wolkoff
A. W.
(
1997
).
Organic anion transporting polypeptide mediates organic anion/HCO3exchange.
J. Biol. Chem
272
,
26340
–.
Schaub
T. P.
,
Kartenbeck
J.
,
Konig
J.
,
Spring
H.
,
Dorsam
J.
,
Staehler
G.
,
Storkel
S.
,
Thon
W. F.
,
Keppler
D.
(
1999
).
Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma.
J. Am. Soc. Nephrol
10
,
1159
–.
Schaub
T. P.
,
Kartenbeck
J.
,
Konig
J.
,
Vogel
O.
,
Witzgall
R.
,
Kriz
W.
,
Keppler
D.
(
1997
).
Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules.
J. Am. Soc. Nephrol
8
,
1213
–.
Sekine
T.
,
Cha
S. H.
,
Tsuda
M.
,
Apiwattanakul
N.
,
Nakajima
N.
,
Kanai
Y.
,
Endou
H.
(
1998
).
Identification of multispecific organic anion transporter 2 expressed predominantly in the liver.
FEBS Lett
429
,
179
–.
Serrano
M. A.
,
Brites
D.
,
Larena
M. G.
,
Monte
M. J.
,
Bravo
M. P.
,
Oliveira
N.
,
Marin
J. J.
(
1998
).
Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta.
J. Hepatol
28
,
829
–.
Shneider
B. L.
,
Dawson
P. A.
,
Christie
D. M.
,
Hardikar
W.
,
Wong
M. H.
,
Suchy
F. J.
(
1995
).
Cloning and molecular characterization of the ontogeny of a rat ileal sodium-dependent bile acid transporter.
J. Clin. Invest
95
,
745
–.
Simon
F. R.
,
Fortune
J.
,
Iwahashi
M.
,
Gartung
C.
,
Wolkoff
A.
,
Sutherland
E.
(
1996
).
Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters.
Am. J. Physiol
271
,
1043
–.
St-Pierre
M. V.
,
Ruetz
S.
,
Epstein
L. F.
,
Gros
P.
,
Arias
I. M.
(
1994
).
ATP-dependent transport of organic anions in secretory vesicles of Saccharomyces cerevisiae.
Proc. Natl. Acad. Sci. USA
91
,
9476
–.
St-Pierre
M. V.
,
Serrano
M. A.
,
Lauper
U.
,
Marin
J. J. G.
,
Meier
P. J.
(
2000
).
Identification of bile salt transporters in human and rat placenta.
Placenta
20
,
64
–.
St-Pierre
M. V.
,
Serrano
M. A.
,
Macias
R. I. R.
,
Dubs
U.
,
Hoechli
M.
,
Lauper
U.
,
Meier
P. J.
,
Marin
J. J. G.
(
2000
).
Expression of members of the multidrug resistance protein family in human term placenta.
Am. J. Physiol
279
,
1495
–.
Stieger
B.
,
Fattinger
K.
,
Madon
J.
,
Kullak-Ublick
G. A.
,
Meier
P. J.
(
2000
).
Drug-and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver.
Gastroenterology
118
,
422
–.
Stieger
B.
,
Hagenbuch
B.
,
Landmann
L.
,
Hochli
M.
,
Schroeder
A.
,
Meier
P. J.
(
1994
).
In situ localization of the hepatocytic Na+/taurocholate cotransporting polypeptide in rat liver.
Gastroenterology
107
,
1781
–.
Stieger
B. B. O. N.
,
Meier
P. J.
(
1992
).
ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles.
Biochem. J
284
,
67
–.
Stiehl
A.
,
Raedsch
R.
,
Rudolph
G.
,
Gundert-Remy
U.
,
Senn
M.
(
1985
).
Biliary and urinary excretion of sulfated, glucuronidated andtetrahydroxylated bile acids in cirrhotic patients.
Hepatology
5
,
492
–.
Strautnieks
S. S.
,
Bull
L. N.
,
Knisely
A. S.
,
Kocoshis
S. A.
,
Dahl
N.
,
Arnell
H.
,
Sokal
E.
,
Dahan
K.
,
Childs
S.
,
Ling
V.
,
Tanner
M. S.
,
Kagalwalla
A. F.
,
Nemeth
A.
,
Pawlowska
J.
,
Baker
A.
,
Mieli-Vergani
G.
,
Freimer
N. B.
,
Gardiner
R. M.
,
Thompson
R. J.
(
1998
).
A gene encoding a liver-specific ABC transporter is mutated in progressive familial intra-hepatic cholestasis.
Nature Genetics
20
,
233
–.
Stravitz
R. T.
,
Sanyal
A. J.
,
Pandak
W. M.
,
Vlahcevic
Z. R.
,
Beets
J. W.
,
Dawson
P. A.
(
1997
).
Induction of sodium-dependent bile acid transporter messenger RNA, protein and activity in rat ileum by cholic acid.
Gastroenterology
113
,
1599
–.
Stroup
D.
,
Crestani
M.
,
Chiang
J. Y.
(
1997
).
Identification of a bile acid response element in the cholesterol 7 alpha-hydroxylase gene CYP7A.
Am. J. Physiol
273
,
508
–.
Trauner
M.
,
Arrese
M.
,
Lee
H.
,
Boyer
J. L.
,
Karpen
S. J.
(
1998
).
Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.
J. Clin. Invest
101
,
2092
–.
van Montfoort
J. E.
,
Hagenbuch
B.
,
Fattinger
K. E.
,
Muller
M.
,
Groothuis
G. M.
,
Meijer
D. K.
,
Meier
P. J.
(
1999
).
Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations.
J. Pharmac. Exp. Ther
291
,
147
–.
Vos
T. A.
,
Hooiveld
G. J.
,
Koning
H.
,
Childs
S.
,
Meijer
D. K.
,
Moshage
H.
,
Jansen
P. L.
,
Muller
M.
(
1998
).
Upregulation of the multidrug resistance genes, Mrp1 and Mdr1b and downregulation of the organic anion transporter, Mrp2 and the bile salt transporter, Spgp, in endotoxemic rat liver.
Hepatology
28
,
1637
–.
Walters
H. C.
,
Craddock
A. L.
,
Fusegawa
H.
,
Willingham
M. C.
,
Dawson
P. A.
(
2000
).
Expression, transport properties and chromosomal location of organic anion transporter subtype 3.
Am. J. Physiol
279
,
1188
–.
Warskulat
U.
,
Kubitz
R.
,
Wettstein
M.
,
Stieger
B.
,
Meier
P. J.
,
Haussinger
D.
(
1999
).
Regulation of bile salt export pump mRNA levels by dexamethasone and osmolarity in cultured rat hepatocytes.
Biol. Chem
380
,
1273
–.
Weinberg
S. L.
,
Burckhardt
G.
,
Wilson
F. A.
(
1986
).
Taurocholate transport by rat intestinal basolateral membrane vesicles. Evidence for the presence of an anion exchange transport system.
J. Clin. Invest
78
,
44
–.
Weinman
S. A.
(
1997
).
Electrogenicity of Na+-coupled bile acid transporters.
Yale J. Biol. Med
70
,
331
–.
Weinman
S. A.
,
Carruth
M. W.
,
Dawson
P. A.
(
1998
).
Bile acid uptake via the human apical sodium—bile acid cotransporter is electrogenic.
J. Biol. Chem
273
,
34691
–.
Wilson
F. A.
,
Burckhardt
G.
,
Murer
H.
,
Rumrich
G.
,
Ullrich
K. J.
(
1981
).
Sodium-coupled taurocholate transport in the proximal convolution of the rat kidney in vivo and in vitro.
J. Clin. Invest
67
,
1141
–.
Wong
M. H.
,
Oelkers
P.
,
Craddock
A. L.
,
Dawson
P. A.
(
1994
).
Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter.
J. Biol. Chem
269
,
1340
–.
Wong
M. H.
,
Oelkers
P.
,
Dawson
P. A.
(
1995
).
Identification of a mutation in the ileal sodium-dependent bile acid transporter gene that abolishes transport activity.
J. Biol. Chem
270
,
27228
–.
Xu
G.
,
Salen
G.
,
Shefer
S.
,
Tint
G. S.
,
Nguyen
L. B.
,
Chen
T. S.
,
Greenblatt
D.
(
1999
).
Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis.
J. Clin. Invest
103
,
89
–.
Yeh
H. Z.
,
Schteingart
C. D.
,
Hagey
L. R.
,
Ton-Nu
H. T.
,
Bolder
U.
,
Gavrilkina
M. A.
,
Steinbach
J. H.
,
Hofmann
A. F.
(
1997
).
Effect of side chain length on biotransformation, hepatic transport and choleretic properties of chenodeoxycholyl homologues in the rodent: studies with dinorchenodeoxycholic acid, norchenodeoxycholic acid and chenodeoxycholic acid.
Hepatology
26
,
374
–.
Zeng
H.
,
Liu
G.
,
Rea
P. A.
,
Kruh
G. D.
(
2000
).
Transport of amphipathic anions by human multidrug resistance protein 3.
Cancer Res
60
,
4779
–.
Ziegler
K.
,
Lins
W.
,
Frimmer
M.
(
1991
).
Hepatocellular transport of cyclosomatostatins: evidence for a carrier system related to the multispecific bile acid transporter.
Biochim. Biophys. Acta
1061
,
287
–.
This content is only available via PDF.