Letters to Nature

Nature 421, 75-79 (2 January 2003) | doi:10.1038/nature01250; Received 30 July 2002; Accepted 7 October 2002

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

Laurent O. Martinez1, Sébastien Jacquet1, Jean-Pierre Esteve2, Corinne Rolland1, Elena Cabezón3, Eric Champagne4, Thierry Pineau5, Valérie Georgeaud1, John E. Walker3, François Tercé1, Xavier Collet1, Bertrand Perret1 & Ronald Barbaras1

  1. Institut Fédératif de Recherche Claude de Preval, IFR 30, Institut National de la Santé et de la Recherche Médicale, Unité 563, Département Lipoprotéines, et Médiateurs Lipidiques, Toulouse cedex, France
  2. Département Immunologie Moléculaire et Biologie du Lymphocyte T, 31059, Toulouse cedex, France
  3. Institut Fédératif de Recherche Louis Bugnard, IFR 31, Institut National de la Santé et de la Recherche Médicale, Unité 531, Biologie et Pathologie Digestive, Hôpital Rangueil, 31403, Toulouse cedex, France
  4. Medical Research Council Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK
  5. Institut National de la Recherche Agronomique, Laboratoire de Pharmacologie et Toxicologie, 31931, Toulouse cedex 9, France

Correspondence to: Ronald Barbaras1 Correspondence and requests for materials should be addressed to R.B. (e-mail: Email: Ronald.Barbaras@toulouse.inserm.fr).

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 beta-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.