ABCMdb

PMID: 14699511

Kullak-Ublick GA, Stieger B, Meier PJ
Enterohepatic bile salt transporters in normal physiology and liver disease.
Gastroenterology. 2004 Jan;126(1):322-42., [PubMed]

Sentences

No. Mutations Sentence Comment

117 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1268Gln ABCB11 p.Arg1268Gln ABCB11 p.Gly238Val ABCB11 p.Gly238Val ABCB11 p.Arg1153Cys ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Gly982Arg ABCB11 p.Cys336Ser It is caused by mutations of the BSEP (ABCB11) gene, which is located on chromosome 2q 24.173 Children with PFIC2 do not express BSEP.174 When PFIC2-related BSEP mutations are introduced artificially into rat Bsep and expressed in Madin-Darby canine kidney and Sf9 insect cells, the G238V, E297G, G982R, R1153C, and R1268Q mutations prevent the protein from trafficking to the apical membrane, whereas the G238V mutant seems to be rapidly degraded by proteasomes.175 Whereas mutation C336S affects neither Bsep transport activity nor trafficking, mutations E297G, G982R, R1153C, and R1268Q abolish taurocholate transport activity. Login to comment 119 ABCB11 p.Glu297Gly ABCB11 p.Arg432Thr A clinical syndrome with recurrent intrahepatic cholestasis but normal liver architecture in an adolescent patient has been associated with compound heterozygosity for the E297G and a novel R432T mutation,176 suggesting that certain adult forms of cholestasis may also be caused by BSEP mutations and reduced transport function. Login to comment 131 ABCC2 p.Ile1173Phe ABCC2 p.Ile1173Phe The syndrome is caused by the absence of MRP2 protein from the canalicular hepatocyte membrane182 because of mutations of the MRP2 gene (ABCC2).181,183,184 The MRP2Delta(R,M) mutation, which describes the deletion of Arg1392 and Met1393, causes disturbed maturation and trafficking of the protein from the endoplasmic reticulum to the Golgi complex and impaired sorting of the glycoprotein to the apical membrane.185 The MRP2 I1173F mutation, which denotes the exchange of the hydrophobic amino acid isoleucine 1173 with phenylalanine in a predicted extracellular loop of MRP2, leads to retention of MRP2 in the endoplasmic reticulum and degradation by proteasomes in transfected HEK293 cells, and is associated with a loss of ATP-dependent transport of leukotriene C4.186 Absent MRP2 function may be compensated for by increased expression of MRP3 at the basolateral hepatocyte membrane, as suggested by immunofluorescence studies on liver sections from a Dubin-Johnson patient.61 Polymorphisms of basolateral bile salt transporter genes. Login to comment 141 ABCB11 p.Glu297Gly ABCB11 p.Arg432Thr Role of Bile Salt Transporters in the Pathogenesis of Liver Disease Species Transport protein Gene symbol Physiologic function Alterations in liver disease References Basolateral transport proteins Rat Ntcp Slc10a1 Naϩ-dependent hepatocellular bile salt uptake Decreased expression in rat models of cholestasis Decreased mRNA and protein levels during pregnancy, associated with decreased nuclear binding of HNF1␣ and RAR␣:RXR␣ 201,211,231 232 Human NTCP SLC10A1 Naϩ-dependent hepatocellular bile salt uptake Decreased mRNA and protein levels in human cholestatic liver disease 30,187 Decreased expression in HCC 72 Rat Oatp1 Slc21a1 Multispecific uptake of organic anions and amphipathic compounds Decreased expression in bile duct ligation and in ethinyl estradiol induced cholestasis 211,233 Oatp2 Slc21a5 Multispecific uptake of organic anions and of cardiac glycosides (digoxin) Decreased mRNA but not protein levels in carbon tetrachloride induced liver injury Decreased mRNA and protein levels in ethinylestradiol-induced cholestasis 234 126 Oatp4 Slc21a10 Multispecific uptake of organic anions and amphipathic compounds Decreased expression in bile duct ligation and sepsis 235 Human OATP-C SLC21A6 Hepatocellular uptake of bile salts and other organic anions Reduced mRNA in PSC and inflammatory cholestasis Decreased expression in HCC 29,30 217 OATP8 SLC21A8 Hepatocellular uptake of organic anions, peptides, and xenobiotics Decreased expression in HCC because of increased expression of the transcriptional repressor HNF3beta 218 Rat/human Mrp1/MRP1 ABCC1 Efflux of cytotoxic cations and non-bile salt organic anions Increased expression in hepatoma cells and sepsis 199,236 Rat/human Mrp3/MRP3 ABCC3 Efflux of organic anions, bile salts, and anticancer agents Increased expression in Eisai Hyperbilirubinemic Rats and in bile duct ligation Increased expression in Dubin-Johnson syndrome and primary biliary cirrhosis 237 61 Hepatocyte canalicular transport proteins Mouse/rat/ human Bsep/Bsep/ BSEP ABCB11 Canalicular efflux of bile salts Gene mutations and absence of the protein in patients with PFIC2, characterized by low GGT levels and reduced biliary bile acid excretion 174,238 Compound heterozygosity for the E297G/R432T mutations in a patient with recurrent intrahepatic cholestasis 176 Reduced mRNA and canalicular BSEP staining in human inflammatory cholestasis 30 Cisinhibition by cholestatic drugs such as cyclosporine A 190 Transinhibition by the cholestatic estrogen metabolite estradiol-17beta-D-glucuronide 190,239 Increased expression in C57L/J gallstone-susceptible mice, despite reduced bile salt excretory capacity 220,240 Mouse/rat/ human Mdr2/Mdr2/ MDR3 ABCB4 Biliary excretion of phospholipids Mdr2 -/- knockout mice exhibit an absence of phospholipids in bile and develop progressive liver disease with portal inflammation, bile duct proliferation and fibrosis 241 PFIC3, characterized by high GGT levels and absent lipoprotein X in serum, is caused by mutations in the MDR3 gene (chromosome 7q21) 177 MDR3 mutations in PFIC3 are associated with intrahepatic cholestasis of pregnancy 242 Rat/human Mrp2/MRP2 ABCC2 Canalicular excretion of organic anions Decreased mRNA and protein levels in bile duct ligation and endotoxinemia 200,243 Decreased canalicular density of Mrp2 transporter molecules in endotoxinemia, taurolithocholate cholestasis, and bile duct ligation 145,200,243 Mutations in the rat Mrp2 gene cause hereditary conjugated hyperbilirubinemia 244 Mutations in the human MRP2 gene cause the Dubin-Johnson syndrome with absent protein expression 181,183 MRP2 function is inhibited by anabolic 17␣-alkylated steroids 245,246 Decreased canalicular MRP2 staining in PBC and inflammatory cholestasis 30,31 Decreased mRNA levels in PSC 29 Human FIC1 ATP8B1 Putative aminophospholipid translocator P-type ATPase, positional candidate in genetic linkage analysis of PFIC1 (Byler`s disease) and BRIC 171 PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis. 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