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Researchers in Canada have helped explain how the PCSK9 protein breaks down receptors for low-density lipoprotein (LDL). Their findings add a key insight into understanding how atherosclerosis develops. The most cholesterol-rich particles in the blood, LDLs are strongly associated with cardiovascular disease. But PCSK9 also plays a role in cancer.
The research 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 professor of medicine at the Université de Montréal.
There is great interest in finding new markers and treatments for atherosclerosis, which is thought to affect more than 27.5% of people over the age of 30 worldwide, according to a recent report in The Lancet. Atherosclerotic heart disease is one of the leading causes of death in the world.
Low-density lipoproteins can accumulate in the blood and lead to atherosclerosis and heart disease. The level of LDL and its associated cholesterol (LDLc) is directly modulated by the ability of LDL receptors (LDLR) to collect LDL from the bloodstream and internalize it, mainly in liver cells. The surface LDLR drives the 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 associated with LDLR dysfunction. But rarer cases are linked to the protein PCSK9, which Seidah’s lab discovered in 2003. PCSK9 is also present in the bloodstream, where it binds to the LDLR and promotes its degradation by liver cells, preventing it from returning to the surface to trap LDL. Some patients with hypercholesterolemia have “super PCSK9” that enhances the breakdown of LDLR.
Recently, highly effective treatments have become available to patients that inhibit the function or reduce the level of PCSK9 in the bloodstream, leading to greater amounts of LDLR, which provide a reduction in LDLc of more than 60 percent compared to conventional statins.
The latest work by Seidah and colleagues elucidates a previously misunderstood mechanism by which PCSK9 drags LDLR to lysosomes, where cells degrade the PCSK9-LDLR complex.
He and his team performed structural analyzes that revealed the formation of a complex of three PCSK9 partner proteins, including LDLR, CAP1 and HLA-C. A key protein in the immune system, HLA-C, was found to direct the entire complex to lysosomes. HLA-C enables the recognition of “self” and also stimulates the antitumor activity of T-lymphocytes. Meanwhile, PCSK9 helps protect against tumor growth and associated metastases by increasing the level of HLA-C on the cell surface.
Ultimately, we hope that inhibitors can be developed to prevent the interaction of PCSK9 and HLA-C and block the function of PCSK9 on LDLR and HLA-C. This breakthrough can then be applied in clinical practice to treat cardiovascular pathologies as well as various types of cancer and metastases in patients.
This work was carried out in collaboration with Carole Fruchart Gaillard and colleagues from the Department of Medicines and Health Technologies at the Université de Paris-Saclay, as well as scientists from the Department of Pharmacy at the University of Pisa, Italy.
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