Copyright ©The Author(s) 2001.
World J Gastroenterol. Apr 15, 2001; 7(2): 157-169
Published online Apr 15, 2001. doi: 10.3748/wjg.v7.i2.157
Table 1 Role of hepatocellular transport proteins in the pathogenesis of liver disease
SpeciesTransport proteinGene symbolPhysiologic functionAlteration in liver disease
Basolateral transport proteins
Rat/humanNtcp/NTCPSLC10A1Na+ dependent bile salt uptakeDecreased Ntcp expression in rat models of cholestasis[25,26,34]
Decreased NTCP expression in human cholestatic liver disease[35]
RatOatp1Slc21a1Multispecific uptake of organic anionsDecreased Oatp1 expression in bile duct ligation[32] and in ethinyl
and amphipathic compoundsestradiol induced cholestasis[34]
Oatp2Slc21a5Multispecific uptake of organic anionsNot yet investigated
and of cardiac glycosides (digoxin)
Oatp4Slc21a10Multispecific uptake of organic anionsDecreased Oatp4 expression in bile duct ligation and sepsis[59]
and amphipathic compounds
HumanOATP-ASLC21A3Multispecific uptake of organic anionsIncreased mRNA levels in primary sclerosing cholangitis (PSC)[180]
and amphipathic compounds
OATP-BSLC21A9Multispecific uptake of organic anionsNot yet investigated
and amphipathic compounds
OATP-CSLC21A6Multispecific uptake of organic anionsDecreased mRNA levels in primary sclerosing cholangitis[181]
and amphipathic compoundsNot yet investigated
OATP8SLC21A8Multispecific uptake of organic anions
and amphipathic compounds
Rat/humanrOCT1/hOCT1SLC22A1Uptake of small hydrophilic organicNot yet investigated
cations (TEA, MPP, choline, dopamine)
RatOAT2SLC22A7Uptake of glutarate, salicylates,Not yet investigated
methotrexate, PGE2 and PAH
RatOAT3SLC22A8Uptake of PAH, estrone-3-sulfate,Not yet investigated
ochratoxin A, cimetidine
Rat/humanMrp1/MRP1ABCC1Efflux of cytotoxic cations andIncreased expression in hepatoma cells[85] and sepsis[182]
non-bile salt organic anions
Rat/humanMrp3/MRP3ABCC3Efflux of organic anions, bile saltsIncreased Mrp3 expression in Eisai Hyperbilirubinemic Rats and
and anticancer agentsin bile duct ligation[91]
Increased MRP3 expression in Dubin-Johnson syndrome and
primary biliary cirrhosis[86]
Rat/humanMrp6/MRP6ABCC6Efflux of BQ-123Not yet investigated
Canalicular Transport Proteins
Mouse/rat/mBsep/Bsep/BSEPABCB11Canalicular efflux of bile saltsMutations in the BSEP gene and absence of the protein in patients
Humanwith PFIC2, characterized by low γ -GT levels and reduced biliary
bile acid excretion[103,110]
Cis-inhibition by cholestatic drugs such as cyclosporine A[172]
Trans-inhibition by the cholestatic estrogen metabolite estradiol-
17β− D-glucuronide[172,175]
Increased mBsep expression in C57L/J gallstone-susceptible
mice, despite reduced bile salt excretory capacity[107,109]
Mouse/rat/Mdr2/Mdr2/MDR3ABCB4Biliary excretion of phospholipidsMdr2-/- knockout mice exhibit an absence of phospholipids in bile
and develop progressive liver disease with portal inflammation,
bile duct proliferation and fibrosis[123]
PFIC3, characterized by high γ -GT levels and absent lipoprotein
X in serum, is caused by mutations in the MDR3 gene
(chromosome 7q21)[143]
MDR3 mutations in PFIC3 are associated with intrahepatic
cholestasis of pregnancy[171]
Rat/humanMrp2/MRP2ABCC2Canalicular excretion of organic anionsDecreased Mrp2 mRNA and protein levels in bile duct ligation and
Decreased canalicular density of Mrp2 transporter molecules in
endotoxinemia[183], taurolithocholate cholestasis[184]
and bile duct ligation[154]
Mutations in the rat Mrp2 gene cause hereditary conjugated
Mutations in the human MRP2 gene cause the Dubin-Johnson
syndrome with absent protein expression[147,149]
MRP2 function is inhibited by anabolic 17á-alkylated
Decreased MRP2 mRNA but unchanged protein levels in PBC[187]
Decreased MRP2 mRNA levels in PSC[181]
HumanFIC1ATP8B1Putative aminophospholipidP-type ATPase, positional candidate in genetic linkage analysis of
translocatorPFIC1 (Byler’s disease) and BRIC[141]
HumanAE2SLC4A2Canalicular Cl-/HCO3- exchangeDecreasedAE2 expression on the luminal surface of cholangiocytes in
PBC (increased expression secondary to UDCA treatment)[188]