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Major scientific advancement in the control of blood cholesterol

December 17, 2015

Montreal, December 17th 2015 – In a study published in the prestigious scientific journal Cell Reports, the research team of Dr. Gaétan Mayer, director of the molecular cell biology laboratory at the Montreal Heart Institute and professor of medicine at Université de Montréal, identified a liver protein that protects the receptor responsible of eliminating circulating LDL-cholesterol, the “bad cholesterol”, from degradation by the protein PCSK9.

Liver cells have a receptor, the LDLR, that eliminates LDL-cholesterol from the bloodstream, the major cause of premature atherosclerosis and cardiovascular diseases. However, they also produce and secrete large amounts of PCSK9, a protein that binds and induces LDLR degradation thereby increasing LDL-cholesterol in the blood. Steve Poirier, postdoctoral fellow and first author of this article, Maya Mamarbachi, research assistant, Gaétan Mayer and their collaborators at the University of Southern California have identified GRP94 as a PCSK9-inhibitory binding protein that naturally prevents complete degradation of the LDLR in the liver. When added outside of the cell as a therapeutic, GRP94 or a fragment thereof were capable of blocking PCSK9 binding to LDLR and prevented degradation of the receptor.

It is now undeniable that PCSK9 is a prime therapeutic target to reduce LDL-cholesterol, a major risk factor for heart attacks and stroke. Indeed, mutations that inactivate the gene PCSK9 provide almost complete protection against cardiovascular diseases by reducing by more than 80% the level of circulating LDL-cholesterol. Based on extensive clinical trials, the European Medicines Agency, the U.S. Food and Drug Administration and Health Canada recently approved the use of antibodies directed against PCSK9 as lipid-lowering therapeutic agents that reduce LDL-cholesterol to unprecedented levels without any apparent side effect. Similarly, this fundamental discovery on the physiological inhibition of PCSK9 by GRP94 opens the door to a new LDL-cholesterol therapeutic approach targeting PCSK9 also intending to reduce the risk of cardiovascular diseases.

New functions of PCSK9 identified
In another study performed by his team, Dr. Gaétan Mayer has identified a new target for proprotein convertase PCSK9. PCSK9 plays a key role in the regulation of cholesterol since it is inversely related to LDL-cholesterol, or “bad cholesterol”, particle clearance from the bloodstream. Elevated LDL-cholesterol level in the plasma is a major risk factor of heart disease and stroke and the use of PCSK9 inhibitors aimed at reducing hypercholesterolemia could prevent major cardiovascular events.

In a study published in the prestigious scientific journal Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), the team discovered that a major receptor involved in transport and storage of fatty acids, FAT/CD36 receptor, is a target of PCSK9. Binding of PCSK9 to cell surface FAT/CD36 receptor leads to its degradation, which reduces internalization of fatty acids. The researchers have studied laboratory mice and found that the absence of PCSK9 increases FAT/CD36 levels and the build-up of fat in the liver of aging mice. The newly identified target is also a gatekeeper of fatty acid entry in the adipose tissue of the abdomen and plays central roles in obesity and type 2 diabetes.

Thus, in addition to its well-known role in hypercholesterolemia, PCSK9 might serve to limit the entry of fatty acids in tissues such as the liver and adipose tissue. Since PCSK9 has become a new hope for high cholesterol treatment and also because two PCSK9 inhibiting drugs have been approved this year by Santé Canada, the U.S. Food and Drug Administration and the European Commission, it appears important to identify all the possible mechanisms of action of PCSK9. In this regard, the discovery of Dr. Mayer and colleagues provides new insights into PCSK9 function in regulating lipid storage in the body.

Dr Mayer’s research was supported by the Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation (HSFC), Canadian Foundation for Innovation (CFI) and the Montreal Heart Institute Foundation (FICM).

  • Reference : Poirier S, Mamarbachi M, Chen WT, Lee AS, Mayer G. GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation. Cell Reports. 2015, 13:1-8. PubMed PMID: 26628375. http://dx.doi.org/10.1016/j.celrep.2015.11.006 
  • Reference : Demers A, Samami S, Lauzier B, Des Rosiers C, Sock ET, Ong H, Mayer G. PCSK9 Induces CD36 Degradation and Affects Long-Chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver. Arterioscler Thromb Vasc Biol. 2015, 35:2517-2525. PubMed PMID: 26494228.

About the Montreal Heart Institute
Founded in 1954 by Dr. Paul David, the Montreal Heart Institute (MHI) constantly aims for the highest standards of excellence in the cardiovascular field through its leadership in clinical and basic research, ultra-specialized care, professional training and prevention. The MHI is affiliated with the Université de Montréal. Research Infosource ranks the Montreal Heart Institute the number one research hospital in Canada for research intensity and research income per researcher.

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SOURCE: Montreal Heart Institute

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