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- Abstract: found
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Clinical application of transcriptional activators of bile salt transporters ☆
review-article
1 June 2014
ABC, ATP-binding cassette,
AE2 (SLC4A2), anion exchanger 2,
ALT, alanine aminotransferase,
AMPK, AMP-activated protein kinase,
ALP, alkaline phosphatase,
ASBT (SLC10A2), apical sodium-dependent bile acid transporter,
ASCOM, activating signal cointegrator-2-containing complex,
BCRP (ABCG2), breast cancer resistance protein,
BRIC2, benign recurrent intrahepatic cholestasis type 2,
BS, bile salt,
BSEP (ABCB11), bile salt export pump,
CA, cholic acid,
cAMP, cyclic adenosine monophosphate,
CARM1, co-activator-associated arginine methyltransferase 1,
CBDL, common bile duct ligation,
CCl4, carbone tetrachloride,
CDCA, chenodeoxycholic acid,
CtBP, C-terminal binding protein,
DCA, deoxycholic acid,
DILI, drug-induced liver injury,
GCA, glycocholic acid,
GGT, gamma-glutamyl transpeptidase,
GR (NR3C1), glucocorticoid receptor,
GRE, glucocorticoid response element,
HNF1α, hepatocyte nuclear factor 1 alpha,
HNF4α, hepatocyte nuclear factor 4 alpha,
ICP, intrahepatic cholestasis of pregnancy,
IL-1β, interleukin-1 beta,
IL-6, interleukin 6,
IR-1, inverse repeat 1,
FGF19/FGF15, fibroblast growth factor 19/15,
FXR, farnesoid X receptor (NR1H4),
FXRE, FXR response element,
JNK, c-Jun N-terminal kinase,
LCA, litocholic acid,
LRH1 (NR5A2), liver receptor homologue 1,
LPS, lipopolysaccharide,
LXR (NR1H3), liver X receptor,
MAF, musculo-aponeurotic fibrosacroma,
MARE, MAF recognition element,
MCL-1, myeloid cell leukemia factor 1,
MDR1 (ABCB1), multidrug resistance protein 1,
MDR2 (ABCB4), multidrug resistance protein 2,
MRP2 (ABCC2), multidrug resistance-associated protein 2,
MRP3 (ABCC3), multidrug resistance-associated protein 3,
MRP4 (ABCC4), multidrug resistance-associated protein 4,
NDRG2, NMYC downstrean-regulated gene 2,
NF-κB, nuclear factor kappa-B,
NRF2, nuclear factor erythroid 2-related factor 2,
NTCP (SLC10A1), Na+-taurocholate cotransporting polypeptide solute carrier family 10 member 1 ,
OATP, organic anion transporting polypeptide,
OCA, obeticholic acid,
OSTα/OSTβ (SLC51A/SLC51B), organic solute transporter alpha/beta,
PBC, primary biliary cirrhosis,
PFIC2, progressive familial intrahepatic cholestasis type 2,
PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha,
PL, phospholipid,
PPARα (NR1C1), peroxisome proliferator-activated receptor alpha,
PPARγ (NR1C3), peroxisome proliferator-activated receptor gamma,
PSC, primary sclerosing cholangitis,
PXR (NR1I2), pregnane X receptor,
RARα (NR1B1), retinoic acid receptor,
RXRα (NR2B1), retinoid X receptor,
SHP (NR0B2), short heterodimer partner,
SRC2, steroid receptor co-activator 2,
SREBP1, sterol regulatory element-binding protein 1,
STAT-5, signal transducer and activator of transcription 5,
TαMCA, α-tauromuricholic acid,
TβMCA, β-tauromuricholic acid,
TCA, taurocholic acid,
TCDCA, taurochenodeoxycholic acid,
TUDCA, tauroursodeoxycholic acid,
TGR5, G protein coupled bile acid receptor,
TNF-α, tumor necrosis factor alpha,
TPN, total parenteral nutrition,
UDCA, ursodeoxycholic acid,
VDR (NR1I1), vitamin D receptor,
VPAC-1, vasoactive intestinal polypeptide activated receptor,
Nuclear receptors,
ATB-binding cassette transporters,
Cholestasis
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Abstract
Hepatobiliary bile salt (BS) transporters are critical determinants of BS homeostasis controlling intracellular concentrations of BSs and their enterohepatic circulation. Genetic or acquired dysfunction of specific transport systems causes intrahepatic and systemic retention of potentially cytotoxic BSs, which, in high concentrations, may disturb integrity of cell membranes and subcellular organelles resulting in cell death, inflammation and fibrosis. Transcriptional regulation of canalicular BS efflux through bile salt export pump (BSEP), basolateral elimination through organic solute transporters alpha and beta (OSTα/OSTβ) as well as inhibition of hepatocellular BS uptake through basolateral Na +-taurocholate cotransporting polypeptide (NTCP) represent critical steps in protection from hepatocellular BS overload and can be targeted therapeutically. In this article, we review the potential clinical implications of the major BS transporters BSEP, OSTα/OSTβ and NTCP in the pathogenesis of hereditary and acquired cholestatic syndromes, provide an overview on transcriptional control of these transporters by the key regulatory nuclear receptors and discuss the potential therapeutic role of novel transcriptional activators of BS transporters in cholestasis.
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Most cited references297
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- Abstract: found
- Article: not found
Identification of a nuclear receptor for bile acids.
M. Makishima, A. Okamoto, J Repa … (1999)
- Record: found
- Abstract: found
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Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.
H. Wang, J. Chen, K Hollister … (1999)
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Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.
G Hayhurst, Y. Lee, G. Lambert … (2001)
Author and article information
abc, atp-binding cassette,ae2 (slc4a2), anion exchanger 2,alt, alanine aminotransferase,ampk, amp-activated protein kinase,alp, alkaline phosphatase,asbt (slc10a2), apical sodium-dependent bile acid transporter,ascom, activating signal cointegrator-2-containing complex,bcrp (abcg2), breast cancer resistance protein,bric2, benign recurrent intrahepatic cholestasis type 2,bs, bile salt,bsep (abcb11), bile salt export pump,ca, cholic acid,camp, cyclic adenosine monophosphate,carm1, co-activator-associated arginine methyltransferase 1,cbdl, common bile duct ligation,ccl4, carbone tetrachloride,cdca, chenodeoxycholic acid,ctbp, c-terminal binding protein,dca, deoxycholic acid,dili, drug-induced liver injury,gca, glycocholic acid,ggt, gamma-glutamyl transpeptidase,gr (nr3c1), glucocorticoid receptor,gre, glucocorticoid response element,hnf1α, hepatocyte nuclear factor 1 alpha,hnf4α, hepatocyte nuclear factor 4 alpha,icp, intrahepatic cholestasis of pregnancy,il-1β, interleukin-1 beta,il-6, interleukin 6,ir-1, inverse repeat 1,fgf19/fgf15, fibroblast growth factor 19/15,fxr, farnesoid x receptor (nr1h4),fxre, fxr response element,jnk, c-jun n-terminal kinase,lca, litocholic acid,lrh1 (nr5a2), liver receptor homologue 1,lps, lipopolysaccharide,lxr (nr1h3), liver x receptor,maf, musculo-aponeurotic fibrosacroma,mare, maf recognition element,mcl-1, myeloid cell leukemia factor 1,mdr1 (abcb1), multidrug resistance protein 1,mdr2 (abcb4), multidrug resistance protein 2,mrp2 (abcc2), multidrug resistance-associated protein 2,mrp3 (abcc3), multidrug resistance-associated protein 3,mrp4 (abcc4), multidrug resistance-associated protein 4,ndrg2, nmyc downstrean-regulated gene 2,nf-κb, nuclear factor kappa-b,nrf2, nuclear factor erythroid 2-related factor 2,ntcp (slc10a1), na+-taurocholate cotransporting polypeptide solute carrier family 10 member 1,oatp, organic anion transporting polypeptide,oca, obeticholic acid,ostα/ostβ (slc51a/slc51b), organic solute transporter alpha/beta,pbc, primary biliary cirrhosis,pfic2, progressive familial intrahepatic cholestasis type 2,pgc-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha,pl, phospholipid,pparα (nr1c1), peroxisome proliferator-activated receptor alpha,pparγ (nr1c3), peroxisome proliferator-activated receptor gamma,psc, primary sclerosing cholangitis,pxr (nr1i2), pregnane x receptor,rarα (nr1b1), retinoic acid receptor,rxrα (nr2b1), retinoid x receptor,shp (nr0b2), short heterodimer partner,src2, steroid receptor co-activator 2,srebp1, sterol regulatory element-binding protein 1,stat-5, signal transducer and activator of transcription 5,tαmca, α-tauromuricholic acid,tβmca, β-tauromuricholic acid,tca, taurocholic acid,tcdca, taurochenodeoxycholic acid,tudca, tauroursodeoxycholic acid,tgr5, g protein coupled bile acid receptor,tnf-α, tumor necrosis factor alpha,tpn, total parenteral nutrition,udca, ursodeoxycholic acid,vdr (nr1i1), vitamin d receptor,vpac-1, vasoactive intestinal polypeptide activated receptor,nuclear receptors,atb-binding cassette transporters,cholestasis
abc, atp-binding cassette, ae2 (slc4a2), anion exchanger 2, alt, alanine aminotransferase, ampk, amp-activated protein kinase, alp, alkaline phosphatase, asbt (slc10a2), apical sodium-dependent bile acid transporter, ascom, activating signal cointegrator-2-containing complex, bcrp (abcg2), breast cancer resistance protein, bric2, benign recurrent intrahepatic cholestasis type 2, bs, bile salt, bsep (abcb11), bile salt export pump, ca, cholic acid, camp, cyclic adenosine monophosphate, carm1, co-activator-associated arginine methyltransferase 1, cbdl, common bile duct ligation, ccl4, carbone tetrachloride, cdca, chenodeoxycholic acid, ctbp, c-terminal binding protein, dca, deoxycholic acid, dili, drug-induced liver injury, gca, glycocholic acid, ggt, gamma-glutamyl transpeptidase, gr (nr3c1), glucocorticoid receptor, gre, glucocorticoid response element, hnf1α, hepatocyte nuclear factor 1 alpha, hnf4α, hepatocyte nuclear factor 4 alpha, icp, intrahepatic cholestasis of pregnancy, il-1β, interleukin-1 beta, il-6, interleukin 6, ir-1, inverse repeat 1, fgf19/fgf15, fibroblast growth factor 19/15, fxr, farnesoid x receptor (nr1h4), fxre, fxr response element, jnk, c-jun n-terminal kinase, lca, litocholic acid, lrh1 (nr5a2), liver receptor homologue 1, lps, lipopolysaccharide, lxr (nr1h3), liver x receptor, maf, musculo-aponeurotic fibrosacroma, mare, maf recognition element, mcl-1, myeloid cell leukemia factor 1, mdr1 (abcb1), multidrug resistance protein 1, mdr2 (abcb4), multidrug resistance protein 2, mrp2 (abcc2), multidrug resistance-associated protein 2, mrp3 (abcc3), multidrug resistance-associated protein 3, mrp4 (abcc4), multidrug resistance-associated protein 4, ndrg2, nmyc downstrean-regulated gene 2, nf-κb, nuclear factor kappa-b, nrf2, nuclear factor erythroid 2-related factor 2, ntcp (slc10a1), na+-taurocholate cotransporting polypeptide solute carrier family 10 member 1, oatp, organic anion transporting polypeptide, oca, obeticholic acid, ostα/ostβ (slc51a/slc51b), organic solute transporter alpha/beta, pbc, primary biliary cirrhosis, pfic2, progressive familial intrahepatic cholestasis type 2, pgc-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha, pl, phospholipid, pparα (nr1c1), peroxisome proliferator-activated receptor alpha, pparγ (nr1c3), peroxisome proliferator-activated receptor gamma, psc, primary sclerosing cholangitis, pxr (nr1i2), pregnane x receptor, rarα (nr1b1), retinoic acid receptor, rxrα (nr2b1), retinoid x receptor, shp (nr0b2), short heterodimer partner, src2, steroid receptor co-activator 2, srebp1, sterol regulatory element-binding protein 1, stat-5, signal transducer and activator of transcription 5, tαmca, α-tauromuricholic acid, tβmca, β-tauromuricholic acid, tca, taurocholic acid, tcdca, taurochenodeoxycholic acid, tudca, tauroursodeoxycholic acid, tgr5, g protein coupled bile acid receptor, tnf-α, tumor necrosis factor alpha, tpn, total parenteral nutrition, udca, ursodeoxycholic acid, vdr (nr1i1), vitamin d receptor, vpac-1, vasoactive intestinal polypeptide activated receptor, nuclear receptors, atb-binding cassette transporters, cholestasis