CARDIF

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

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Coronary artery disease (CAD) resulting from atherosclerosis, the narrowing of arteries due to fatty deposits, causes millions of deaths globally. EU-funded researchers investigated the pathways involved in regulating cholesterol.

Descrizione progetto (Article)

Previous research has indicated that high-density lipoproteins (HDLs) in our plasma have a key positive role to play in reverse cholesterol transport (RCT). RCT helps regulate cholesterol levels and eliminates excess cholesterol via the liver, thus preventing or mitigating the severity of atherosclerosis.

It is known that HDL uptake in the liver occurs via two receptors: scavenger receptor BI and mitochondrial ATP synthase (ecto-F1-ATPase). Ecto-F1-ATPase binds to HDL apolipoprotein A-I causing ATP hydrolysis and activation of the P2Y13 receptor. These processes are critical for HDL uptake in the liver and cholesterol regulation.

The project 'Physiological impact of IF1 inhibitor on reverse cholesterol transport (RCT) and atherosclerosis' (CARDIF) developed new animal models and used experimental tools to investigate the role of F1-ATPase/P2Y13 in RCT.

Results revealed that RCT is impaired in P2Y13-deficient mice. Contrarily, continuous P2Y13 activation for three days reduced plasma HDL cholesterol levels in wild-type mice. Findings suggest that increased activation of P2Y13 would increase risk for atherosclerosis through reduced plasma HDL levels. Analyses of P2Y13-deficient mice on a 16-week high-cholesterol diet groundbreakingly revealed that P2Y13 has a protective effect with regard to atherosclerosis development.

The ATPase inhibitory factor 1 (IF1) is a mitochondrial protein. Studies in mouse models revealed that IF1 inhibits ecto-F1-ATPase activity to modulate RCT and correlates positively with HDL levels. Good IF1 and HDL levels suggest a lower risk for CAD. Hence, IF1 could serve as a biomarker to assess CAD risk.

Project outcomes clearly demonstrate the critical role of the ecto-F1-ATPase/P2Y13 pathway in regulating cholesterol levels through RCT. Until now, pharmaceutical strategies focused on lowering low-density lipoprotein cholesterol levels with limited success in CAD management. Future research endeavours can now focus on using P2Y13 as a therapeutic target to regulate HDL metabolism and arrest atherosclerosis development.