Several large prospective studies established that high-density lipoprotein cholesterol (HDL-C) is an independent negative risk factor for CHD thus representing today’s major protective factor against atherosclerosis, mostly attributable to their roles in ‘Reverse Cholesterol Transport (RCT)’. RCT allows excessive cell cholesterol to be taken up and processed in HDL particles, and later carried to the liver. To identify new cellular partners involved in hepatic HDL-C clearance in human, Martinez et al. recently reported the presence on the cell surface of human hepatocytes of a complex related to the mitochondrial ATP synthase as a high affinity receptor for HDL apolipoprotein A-1. This complex is involved in a cell surface signalization pathway for HDL endocytosis in which apoA-1 binding to the ATP synthase (ectoF1-ATPase) stimulates extracellular ATP hydrolysis into ADP. The newly synthesized ADP specially activates the nucleotide receptor P2Y13 resulting in clathrin-dependent HDL-C endocytosis. P2Y13 deficiency in mice (P2Y13 knock out/Ko) provokes a significant decay in biliary lipids secretions. Studies on P2Y13 Ko mice on atherosclerotic background (apoE Ko) showed that double Ko mice displayed an increased atherosclerosis plaque, compared to apoE-Ko. We aim to study whether regulating the ‘F1-ATPase/ P2Y13’-mediated HDL endocytosis pathway might be a therapeutic target in prevention and treatment of atherosclerosis. The F1-ATPase Inhibitor IF1 (inhibitor factor 1) is a10 KD protein that was shown to inhibit HDL uptake both on human hepatocytes and in situ on perfused rat liver. IF1 was found to be constitutively expressed at the hepatocyte surface, suggesting IF1 physiological role in inhibiting hepatic HDL endocytosis. However, very little is known on the physiological relevance of IF1 in this process. The research project proposes to characterize the physiopathologic role of the inhibitor of F1-ATPase IF1 in HDL-C metabolism and atherosclerosis development.
Field of science
- /social sciences/social and economic geography/transport
- /medical and health sciences/clinical medicine/cardiology/cardiovascular diseases/arteriosclerosis
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