Grant: Travel Awards - Institute Community Support

LDL "bad cholesterol" is largely responsible for the development of heart disease. It main protein, apoB, has correlated strongly with several risk factors associated with cardiovascular disease and diabetes. LDL's concentration in the blood is controlled, in part, by the amount of LDL-receptors on the cell surface which are able to capture and rid the blood of LDL. PCSK9 is a protein that controls the amount of LDL-receptor at the surface by binding to it and helping in its breakdown. Mutations affecting the function of PCSK9 have shown that overly functional PCSK9 leads to fewer LDL-receptors at the cell surface and greater risk of developing cardiovascular disease whereas mutations that deplete the cells of PCSK9 reduce cardiovascular risk. Our work assess whether increased clearance of LDL particle because of low PCSK9 concentrations are beneficial. What we've observed is that when cells, such as fat cells, capture and remove LDL from the circulation, it harms these cells and renders them dysfunctional. Therefore, despite reducing LDL in the blood and lowering the risk of cardiovascular disease, it appears that when LDL is taken up by tissues other than the liver, it harms them. We demonstrate this effect through correlations of risk factors for diabetes and the amount of apoB and PCSK9 in the blood. The more participants cleared LDL because of PCSK9, the more their fat cells appeared dysfunctional. This work therefore demonstrates that we should not simply be concerned with the reduction of LDL, but the method by which this is achieved.