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

Abstract

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.

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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.

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Acknowledgements

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

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Correspondence to Ronald Barbaras.

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The authors declare that they have no competing financial interests.

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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). https://doi.org/10.1038/nature01250

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