Illustration of red blood cells moving through clogged artery to indicate cholesterol build up as a result of familial hypercholesterolemia and atherosclerosis, which are being targeted by Verve Therapeutics
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Researchers in Canada have helped explain how the PCSK9 protein degrades low-density lipoprotein (LDL) receptors. Their findings add key insight to the understanding of how atherosclerosis develops. The richest cholesterol particles in the bloodstream, LDLs are strongly linked to cardiovascular disease. But PCSK9 also plays a role in cancer.

The study is published in the January issue of Molecular Metabolism. It was led by Nabil G. Seidah, director of the biochemical neuroendocrinology research unit at the Montreal Clinical Research Institute and a medical professor at Université de Montréal.

There is great interest in finding new markers and treatments for atherosclerosis, which is estimated to affect more than 27.5% of people aged over 30 worldwide, according to a recent report in The Lancet. Heart disease from atherosclerosis is one of the world’s leading causes of death.

Low density lipoproteins can accumulate in the blood and lead to atherosclerosis and heart disease. The level of LDL and the cholesterol associated with it (LDLc), is directly modulated by the ability of LDL receptors (LDLR) to collect LDL from the bloodstream and internalize it, mainly into the cells of the liver. The surface LDLR drives LDL into the cell where it is captured, and the LDLR returns to the surface for another round of capture.

Most cases of familial hypercholesterolemia are related to LDLR dysfunction. But rarer cases have been linked to the PCSK9 protein, which Seidah’s laboratory’s discovered in 2003. PCSK9 is also present in the bloodstream where it associates with LDLR and promotes its degradation by liver cells, preventing it from returning to the surface to capture LDL. Some hypercholesterolemic patients have a “super PCSK9” that enhances the degradation of the LDLR.

Highly effective treatments have recently become available to patients that inhibit the function or reduce the level of PCSK9 in the bloodstream, resulting in larger amounts of LDLR that ensure a decrease in LDLc of more than 60 per cent compared to conventional statins.

Seidah and his colleagues’ most recent work clarifies the previously misunderstood mechanism by which PCSK9 drags the LDLR towards the lysosomes, where cells degrade the PCSK9-LDLR complex.

He and his team conducted structural analyses that revealed the formation of a complex of three PCSK9 partner proteins, including the LDLR, CAP1, and HLA-C. A key protein in the immune system, HLA-C was found to direct the entire complex to the lysosomes. HLA-C allows the recognition of the “self,” and also stimulates the anti-tumor activity of T lymphocytes. PCSK9, meanwhile, helps protect against the growth of tumors, and associated metastasis, by increasing the level of HLA-C on the cell surface.

Ultimately, it is hoped that inhibitors can be developed that would prevent the interaction of PCSK9 and HLA-C and block the function of PCSK9 on LDLR and HLA-C. That breakthrough could then be applied in clinical practice to treat cardiovascular pathologies as well as various types of cancer and metastases in patients.

This work was done in collaboration with Carole Fruchart Gaillard and colleagues at the Université de Paris-Saclay’s Department of Drugs and Technologies for Health, as well as with scientists in the pharmacy department of the University of Pisa, in Italy.

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