Ectopic β-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis


The effect of high-density lipoprotein (HDL) in protecting against atherosclerosis is usually attributed to its role in ‘reverse cholesterol transport’1. In this process, HDL particles mediate the efflux and the transport of cholesterol from peripheral cells to the liver for further metabolism and bile excretion. Thus, cell-surface receptors for HDL on hepatocytes are chief partners in the regulation of cholesterol homeostasis2. A high-affinity HDL receptor for apolipoprotein A-I (apoA-I) was previously identified on the surface of hepatocytes3,4. Here we show that this receptor is identical to the β-chain of ATP synthase, a principal protein complex of the mitochondrial inner membrane. Different experimental approaches confirm this ectopic localization of components of the ATP synthase complex and the presence of ATP hydrolase activity at the hepatocyte cell surface. Receptor stimulation by apoA-I triggers the endocytosis of holo-HDL particles (protein plus lipid) by a mechanism that depends strictly on the generation of ADP. We confirm this effect on endocytosis in perfused rat liver ex vivo by using a specific inhibitor of ATP synthase. Thus, membrane-bound ATP synthase has a previously unsuspected role in modulating the concentrations of extracellular ADP and is regulated by a principal plasma apolipoprotein.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Affinity purification of the free apoA-I receptor.
Figure 2: Immunofluorescence localization of the β- and α-chains of ATP synthase with apoA-I on the surface of hepatocytes.
Figure 3: Detection of the β-chain of ATP synthase at the cell surface by flow cytometry.
Figure 4: Effect of different nucleotides on internalization of TG-HDL2 by hepatocytes.
Figure 5: Effect of IF1 on TG-HDL2 internalization by hepatocytes.


  1. 1

    Sviridov, D. & Nestel, P. Dynamics of reverse cholesterol transport: protection against atherosclerosis. Atherosclerosis 161, 245–254 (2002)

    CAS  Article  Google Scholar 

  2. 2

    Fidge, N. H. High density lipoprotein receptors, binding proteins, and ligands. J. Lipid Res. 40, 187–201 (1999)

    CAS  PubMed  Google Scholar 

  3. 3

    Barbaras, R., Collet, X., Chap, H. & Perret, B. Specific binding of free apolipoprotein A-I to a high-affinity binding site on HepG2 cells: characterization of two high-density lipoprotein sites. Biochemistry 33, 2335–2340 (1994)

    CAS  Article  Google Scholar 

  4. 4

    Martinez, L. O. et al. Characterization of two high-density lipoprotein binding sites on porcine hepatocyte plasma membranes: contribution of scavenger receptor class B type I (SR-BI) to the low-affinity component. Biochemistry 39, 1076–1082 (2000)

    CAS  Article  Google Scholar 

  5. 5

    Boyer, P. D. The ATP synthase: a splendid molecular machine. Annu. Rev. Biochem. 66, 717–749 (1997)

    CAS  Article  Google Scholar 

  6. 6

    Stock, D., Leslie, A. G. & Walker, J. E. Molecular architecture of the rotary motor in ATP synthase. Science 286, 1700–1705 (1999)

    CAS  Article  Google Scholar 

  7. 7

    Cabezon, E., Runswick, M. J., Leslie, A. G. & Walker, J. E. The structure of bovine IF(1), the regulatory subunit of mitochondrial F-ATPase. EMBO J. 20, 6990–6996 (2001)

    CAS  Article  Google Scholar 

  8. 8

    Das, B., Mondragon, M. O., Sadeghian, M., Hatcher, V. B. & Norin, A. J. A novel ligand in lymphocyte-mediated cytotoxicity: expression of the beta subunit of H + transporting ATP synthase on the surface of tumour cell lines. J. Exp. Med. 180, 273–281 (1994)

    CAS  Article  Google Scholar 

  9. 9

    Moser, T. L. et al. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc. Natl Acad. Sci. USA 96, 2811–2816 (1999)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Chang, S. Y., Park, S. G., Kim, S. & Kang, C. Y. Interaction of the C-terminal domain of p43 and the α subunit of ATP synthase: Its functional implication in endothelial cell proliferation. J. Biol. Chem. 277, 8388–8394 (2001)

    Article  Google Scholar 

  11. 11

    Schippers, I. J. et al. Immortalized human hepatocytes as a tool for the study of hepatocytic (de-)differentiation. Cell Biol. Toxicol. 13, 375–86 (1997)

    CAS  Article  Google Scholar 

  12. 12

    Williams, N., Amzel, L. M. & Pedersen, P. L. Proton ATPase of rat liver mitochondria: a rapid procedure for purification of a stable, reconstitutively active F1 preparation using a modified chloroform method. Anal. Biochem. 140, 581–588 (1984)

    CAS  Article  Google Scholar 

  13. 13

    Moser, T. L. et al. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc. Natl Acad. Sci. USA 98, 6656–6661 (2001)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Beisiegel, U. et al. Apolipoprotein E-binding proteins isolated from dog and human liver. Arteriosclerosis 8, 288–297 (1988)

    CAS  Article  Google Scholar 

  15. 15

    Mahley, R. W., Hui, D. Y., Innerarity, T. L. & Beisiegel, U. Chylomicron remnant metabolism. Role of hepatic lipoprotein receptors in mediating uptake. Arteriosclerosis 9, I14–I18 (1989)

    CAS  PubMed  Google Scholar 

  16. 16

    Ferrini, J. B., Pichard, L., Domergue, J. & Maurel, P. Long-term primary cultures of adult human hepatocytes. Chem. Biol. Interact. 107, 31–45 (1997)

    CAS  Article  Google Scholar 

  17. 17

    Cabezon, E., Arechaga, I., Jonathan, P., Butler, G. & Walker, J. E. Dimerization of bovine F1-ATPase by binding the inhibitor protein, IF1 . J. Biol. Chem. 275, 28353–28355 (2000)

    CAS  Article  Google Scholar 

  18. 18

    Cabezon, E., Butler, P. J., Runswick, M. J. & Walker, J. E. Modulation of the oligomerization state of the bovine F1-ATPase inhibitor protein, IF1, by pH. J. Biol. Chem. 275, 25460–25464 (2000)

    CAS  Article  Google Scholar 

  19. 19

    Guendouzi, K., Collet, X., Perret, B., Chap, H. & Barbaras, R. Remnant high density lipoprotein2 particles produced by hepatic lipase display high-affinity binding and increased endocytosis into a human hepatoma cell line (HEPG2). Biochemistry 37, 14974–14980 (1998)

    CAS  Article  Google Scholar 

  20. 20

    Acton, S. et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518–520 (1996)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Silver, D. L., Nan, W., Xiao, X. & Tall, A. R. HDL particle uptake mediated by SR-BI results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion. J. Biol. Chem. 276, 25287–25293 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Walker, J. E. The regulation of catalysis in ATP synthase. Curr. Opin. Struct. Biol. 4, 912–918 (1994)

    CAS  Article  Google Scholar 

  23. 23

    Wang, N., Silver, D. L., Thiele, C. & Tall, A. R. ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J. Biol. Chem. 276, 23742–23747 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Bortnick, A. E. et al. The correlation of ABC1 mRNA levels with cholesterol efflux from various cell lines. J. Biol. Chem. 275, 28634–28640 (2000)

    CAS  Article  Google Scholar 

  25. 25

    Burgess, J. W., Kiss, R. S., Zheng, H., Zachariah, S. & Marcel, Y. L. Trypsin-sensitive and lipid-containing sites of the macrophage extracellular matrix bind apolipoprotein A-I and participate in ABCA1-dependent cholesterol efflux. J. Biol. Chem. 277, 31318–31326 (2002)

    CAS  Article  Google Scholar 

  26. 26

    Fitzgerald, M. L. et al. Naturally occurring mutations in ABCA1's largest extracellular loops can disrupt its direct interaction with apolipoprotein A-I. J. Biol. Chem. 277, 33178–33187 (2002)

    CAS  Article  Google Scholar 

  27. 27

    Barrans, A. et al. Hepatic lipase induces the formation of pre-β1 high density lipoprotein (HDL) from triacylglycerol-rich HDL2 . J. Biol. Chem. 269, 11572–11577 (1994)

    CAS  PubMed  Google Scholar 

  28. 28

    Johnsson, B., Lofas, S. & Lindquist, G. Immobilization of proteins to a carboxymethyldextran-modified gold surface for biospecific interaction analysis in surface plasmon resonance sensors. Anal. Biochem. 198, 268–277 (1991)

    CAS  Article  Google Scholar 

  29. 29

    Sultan, C. et al. The novel inositol lipid phosphatidylinositol 3,4-bisphosphate is produced by human blood platelets upon thrombin stimulation. Biochem. J. 269, 831–834 (1990)

    CAS  Article  Google Scholar 

Download references


We thank G. Larrieu, for technical help, and P. Maurel INSERMU128, for the primary human hepatocytes.

Author information



Corresponding author

Correspondence to Ronald Barbaras.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Martinez, L., Jacquet, S., Esteve, J. et al. Ectopic β-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature 421, 75–79 (2003).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing