Advertisement

Hepatic cell-specific ATP-binding cassette (ABC) transporter profiling identifies putative novel candidates for lipid homeostasis in mice

  • Dan Ye
    Correspondence
    Corresponding author. Tel.: +31 71 5276238; fax: +31 71 5276032.
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • Menno Hoekstra
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • Ruud Out
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • Illiana Meurs
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • J. Kar Kruijt
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • Reeni B. Hildebrand
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • Theo J.C. Van Berkel
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author
  • Miranda Van Eck
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
    Search for articles by this author

      Abstract

      Background

      ABC-transporters play an important role in lipid trafficking. Therefore, hepatic expression patterns of ABC-transporters involved in the regulation of cholesterol metabolism were evaluated.

      Methods and results

      RT-PCR analysis showed that the mRNA expression of 38 ABC-transporters detected in livers of C57Bl/6 mice varied greatly. Although most ABC-transporters were ubiquitously expressed, some members displayed very restricted expression patterns, e.g. ABCA6, A8, B1, B8, B10, B11, C3, D2, and G5/G8 were exclusively (>99%) expressed in parenchymal cells. Interestingly, another 13 ABC-transporters, including ABCA4, A5, A9, A13, B2, B9, C1, C5, D3, D4, F2, G1, and G4 were primarily expressed in Kupffer cells. Although Kupffer cells only contribute to 2.5% of the total liver protein, these 13 genes did contain 9–27% of the total liver expression. Western-type diet feeding (0.25% cholesterol, 15% fat) induced the expression of several primarily Kupffer cell expressed genes, including ABCA5, B9, D3, and D4 (2 to 3-fold higher), whereas the other ABC-transporters were not significantly changed.

      Conclusions

      Our findings underscore the importance of cellular localization for studying the regulation of key ABC-transporters in liver cholesterol homeostasis. Furthermore, several novel ABC-transporters, including ABCA5, B9, D3, and D4 were identified as putative novel candidates involved in liver macrophage cholesterol homeostasis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Higgins C.F.
        ABC transporters: from microorganisms to man.
        Annu Rev Cell Biol. 1992; 8: 67-113
        • Dean M.
        • Hamon Y.
        • Chimini G.
        The human ATP-binding cassette (ABC) transporter superfamily.
        J Lipid Res. 2001; 42: 1007-1017
        • Rye K.A.
        • Barter P.J.
        Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I.
        Arterioscler Thromb Vasc Biol. 2004; 24: 421-428
        • Klucken J.
        • Buchler C.
        • Orso E.
        • et al.
        ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport.
        Proc Natl Acad Sci USA. 2000; 97: 817-822
        • Jessup W.
        • Gelissen I.C.
        • Gaus K.
        • et al.
        Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages.
        Curr Opin Lipidol. 2006; 17: 247-257
        • Kennedy M.A.
        • Barrera G.C.
        • Nakamura K.
        • et al.
        ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.
        Cell Metab. 2005; 1: 121-131
        • Wang N.
        • Lan D.
        • Chen W.
        • et al.
        ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins.
        Proc Natl Acad Sci USA. 2004; 101: 9774-9779
        • Graf G.A.
        • Li W.P.
        • Gerard R.D.
        • et al.
        Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface.
        J Clin Invest. 2002; 110: 659-669
        • Szakacs G.
        • Annereau J.P.
        • Lababidi S.
        • et al.
        Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells.
        Cancer Cell. 2004; 6: 129-137
        • Dean M.
        • Rzhetsky A.
        • Allikmets R.
        The human ATP-binding cassette (ABC) transporter superfamily.
        Genome Res. 2001; 11: 1156-1166
        • Lawn R.M.
        • Wade D.P.
        • Garvin M.R.
        • et al.
        The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway.
        J Clin Invest. 1999; 104: R25-R31
        • Lorkowski S.
        • Kratz M.
        • Wenner C.
        • et al.
        Expression of the ATP-binding cassette transporter gene ABCG1 (ABC8) in Tangier disease.
        Biochem Biophys Res Commun. 2001; 283: 821-830
        • Hubacek J.A.
        • Berge K.E.
        • Cohen J.C.
        • et al.
        Mutations in ATPcassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.
        Hum Mutat. 2001; 18: 359-360
        • Berge K.E.
        • Tian H.
        • Graf G.A.
        • et al.
        Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
        Science. 2000; 290: 1771-1775
        • Langmann T.
        • Mauerer R.
        • Schmitz G.
        Human ATP-binding cassette transporter TaqMan low-density array: analysis of macrophage differentiation and foam cell formation.
        Clin Chem. 2006; 52: 310-313
        • Hoekstra M.
        • Kruijt J.K.
        • Van Eck M.
        • et al.
        Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer cells.
        J Biol Chem. 2003; 278: 25448-25453
        • Out R.
        • Hoekstra M.
        • Meurs I.
        • et al.
        Total body ABCG1 expression protects against early atherosclerotic lesion development in mice.
        Arterioscler Thromb Vasc Biol. 2007; 27: 594-599
        • Van Velzen A.G.
        • Da Silva R.P.
        • Gordon S.
        • et al.
        Characterization of a receptor for oxidized low-density lipoproteins on rat Kupffer cells: similarity to macrosialin.
        Biochem J. 1997; 322: 411-415
        • Chomczynski P.
        • Sacchi N.
        Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
        Anal Biochem. 1987; 162: 156-159
        • Smit J.J.
        • Schinkel A.H.
        • Oude Elferink R.P.
        • et al.
        Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.
        Cell. 1993; 75: 451-462
        • Langheim S.
        • Yu L.
        • von Bergmann K.
        • et al.
        ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile.
        J Lipid Res. 2005; 46: 1732-1738
        • Maisonnette F.
        • Abita T.
        • Barriere E.
        • et al.
        The MDR3 gene mutation: a rare cause of progressive familial intrahepatic cholestasis (PFIC).
        Ann Chir. 2005; 130: 581-583
        • Wakabayashi Y.
        • Lippincott-Schwartz J.
        • Arias I.M.
        Intracellular trafficking of bile salt export pump (ABCB11) in polarized hepatic cells: constitutive cycling between the canalicular membrane and rab11-positive endosomes.
        Mol Biol Cell. 2004; 15: 3485-3496
        • Thompson R.
        • Strautnieks S.
        BSEP: function and role in progressive familial intrahepatic cholestasis.
        Semin Liver Dis. 2001; 21: 545-550
        • Hashimoto K.
        • Uchiumi T.
        • Konno T.
        • et al.
        Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin–Johnson syndrome.
        Hepatology. 2002; 36: 1236-1245
        • Bakkeren H.F.
        • Kuipers F.
        • Vonk R.J.
        • et al.
        Evidence for reverse cholesterol transport in vivo from liver endothelial cells to parenchymal cells and bile by high-density lipoprotein.
        Biochem J. 1990; 268: 685-691
        • Blomhoff R.
        • Drevon C.A.
        • Eskild W.
        • et al.
        Clearance of acetyl low density lipoprotein by rat liver endothelial cells.
        J Biol Chem. 1984; 259: 8896-8903
        • Pennings M.
        • Meurs I.
        • Ye D.
        • et al.
        Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development.
        FEBS Lett. 2006; 580: 5588-5596
        • Van Eck M.
        • Pennings M.
        • Hoekstra M.
        • et al.
        Scavenger receptor BI and ATP-binding cassette transporter A1 in reverse cholesterol transport and atherosclerosis.
        Curr Opin Lipidol. 2005; 16: 307-315
        • Neufeld E.B.
        • Demosky Jr., S.J.
        • Stonik J.A.
        • et al.
        The ABCA1 transporter functions on the basolateral surface of hepatocytes.
        Biochem Biophys Res Commun. 2002; 297: 974-979
        • Wanders R.J.
        • Visser W.F.
        • van Roermund C.W.
        • et al.
        The peroxisomal ABC transporter family.
        Pflugers Arch. 2007; 453: 719-734
        • Fourcade S.
        • Savary S.
        • Albet S.
        • et al.
        Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2): promoter analysis and role of the peroxisome proliferator-activated receptor PPARalpha.
        Eur J Biochem. 2001; 268: 3490-3500
        • Chinetti G.
        • Fruchart J.C.
        • Staels B.
        Transcriptional regulation of macrophage cholesterol trafficking by PPARalpha and LXR.
        Biochem Soc Trans. 2006; 34: 1128-1131
        • Kubo Y.
        • Sekiya S.
        • Ohigashi M.
        • et al.
        ABCA5 resides in lysosomes, and ABCA5 knockout mice develop lysosomal disease-like symptoms.
        Mol Cell Biol. 2005; 25: 4138-4149
        • Petry F.
        • Ritz V.
        • Meineke C.
        • et al.
        Subcellular localization of rat Abca5, a rat ATP-binding-cassette transporter expressed in Leydig cells, and characterization of its splice variant apparently encoding a half-transporter.
        Biochem J. 2006; 393: 79-87
        • Chen W.
        • Wang N.
        • Tall A.R.
        A PEST deletion mutant of ABCA1 shows impaired internalization and defective cholesterol efflux from late endosomes.
        J Biol Chem. 2005; 280: 29277-29281
        • Neufeld E.B.
        • Stonik J.A.
        • Demosky Jr., S.J.
        • et al.
        The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease.
        J Biol Chem. 2004; 279: 15571-15578