CardIF · Physiological impact of IF1 inhibitor on Reverse Cholesterol Transport (RCT) and atherosclerosis

Physiological impact of IF1 inhibitor on Reverse Cholesterol Transport (RCT) and atherosclerosis

Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol and triglyceride. Atherosclerosis is a leading cause of death in the western world, which is caused by both genetic and environmental risk factors. There is evidence that plasma high-density lipoproteins (HDL) level is an independent negative risk factor (or protective factor) for coronary artery disease (CAD) and atherosclerosis. The best-characterized protective action of HDL is their central contribution in a process called reverse cholesterol transport (RCT). In this process, excess cell cholesterol is taken up from cholesterol loaded macrophages (so-called foam cells) of the arterial wall and processed in HDL particles. Once transported to the liver, it is further eliminated into the bile as free cholesterol or after conversion into bile acids, leading to a reduction of atherosclerosis-lesion size. HDL are removed from the circulation by at least two direct pathways for HDL uptake by the liver, which involve two receptors. The first one is the scavenger receptor BI (SR-BI) that mediates cholesterol uptake from the HDL particle in a selective way. The second receptor has been identified by our laboratory in 2003; we reported that a complex related to the mitochondrial ATP synthase (ecto-F1-ATPase) is a high affinity receptor for HDL apolipoprotein A-I (apoA-I, the major protein of HDL) involved in the uptake of both protein and lipid moieties of the HDL particle, a process called holo-HDL endocytosis. More precisely, the binding of apoA-I to the ecto-F1-ATPase stimulates extracellular ATP hydrolysis into ADP. The generation of extracellular ADP specifically activates the purinergic P2Y13 receptor, resulting in subsequent HDL endocytosis through low-affinity binding sites distinct from SR-BI. We demonstrated that hallmark features of RCT are impaired in P2Y13-deficient mice. On the other hand, continuous activation of P2Y13, for 3 days, markedly increased the elimination of HDL particles from the circulation by the liver and decreased plasma HDL-cholesterol level, in vivo in wild-type mice. These results might be attributed to P2Y13 action in stimulating HDL uptake by the liver, resulting in an accelerated HDL clearance from the circulation. As such, increasing the activity of P2Y13 should have an anti-atherogenic effect. An alternative hypothesis would suggest that increased activity of P2Y13 should increase susceptibility to atherosclerosis by decreasing HDL-cholesterol plasma concentration. These results are published in BBA lipids, USA. Analyses of the effect of long-term cholesterol intake on P2Y13 deficient mice fed a high cholesterol diet for 16 weeks, and of the effect of P2Y13 deletion on atherosclerosis development on apoE background suggest that P2Y13 is suitable as a target for therapeutic intervention targeting HDL metabolism. These experiments argue in favour of a protective effect on P2Y13 toward atherosclerosis development. We are the first to describe this phenomena. These results will be submitted for publication in Hepatology, USA, within next few months. IF1, the ATPase inhibitory factor 1, is a mitochondrial protein that when isolated inhibits the ecto-F1-ATPase activity. Interestingly, exogenous IF1 was able to reduce by about 50% HDL uptake by perfused rat liver. We recently developed an Elisa test allowing quantization of IF1 in human serum. We showed that IF1 is present in serum and correlates positively with HDL-cholesterol (HDL-C). Furthermore, we showed that IF1 is negatively associated with coronary heart disease. Overall these data argue in favor of IF1 being a new determinant of HDL levels and potential biomarker of cardiovascular risk. In line with these data, we developed mouse models to study IF1 role in HDL uptake by the liver. We suggest that IF1 acts constitutively in vivo on RCT by inhibiting ectoF1-ATPase. These results are published in the Journal of Lipid Research, USA. Altogether, these data highlight the importance of the ecto-F1-ATPase/P2Y13 pathway in reverse cholesterol transport. Its modulation brings a new approach in fight against CAD. Relevance of the project : Coronary heart disease (CHD) due to atherosclerosis is now the leading cause of mortality and morbidity in Europe, each year CHD causes an estimated 17 million deaths worldwide, accounting for one-third of all deaths worldwide. High level of HDL-cholesterol is known to be protective, mainly due to the ability of these lipoproteins to eliminate excess cholesterol from the body through a process called “Reverse Cholesterol Transport” (RCT). Conversely, impaired HDL-mediated RCT increases atherosclerosis. In this proposal, we aimed to study, in a whole animal context, the regulation of a new pathway for hepatic HDL-C uptake (namely ‘F1-ATPase/P2Y13’) involved in RCT. Briefly, using unique experimental tools available in the team and developing new animal models, we evaluated the contribution of the ‘F1ATPase/P2Y13’ low affinity component modulation, in vivo, following two different approaches. Our work brings a better understanding of P2Y13 role in HDL metabolism in a context of chronicle activation as well as in the field of atherosclerosis development. Thus, the accomplishment of this project evidence new pharmacological approaches in HDL-related therapies, with the ultimate goal to protect against atherosclerosis development and CHD. Therefore, this proposal is significant for both basic and applied research. Benefit at the community level Whereas lowering LDL-C is possible since 1987 with the approval of the first blockbuster Merck’s statin, coronary events still occur at a high rate and many tentative therapies have been done to target HDL but with no success yet. Thus, the results of this proposal open a window on new pharmacological strategies with the ultimate goal to protect against atherosclerosis development.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз