Grant: Travel Awards - Institute Community Support

Cardiovascular disease (CVD) causes one-third of deaths in Canada and represents approximately $22 billion in health care costs and lost productivity annually. One of risk factor for CVD is hypertriglyceridemia (HTG), which is the medical term for a high level of triglycerides (TG) in blood, due mainly to an unhealthy diet and lifestyle. The TG found in the bloodstream are broken down by an enzyme called lipoprotein lipase (LPL). The latter requires activation by an protein called apolipoprotein A5 (ApoA5). Through this mechanism, circulating TG levels are decreased due to their storage in liver or fat cells called adipose cells. Recently, genetic evidence suggested that another enzyme named proprotein convertase 7 (PCSK7) could modulate circulating TG levels. A mouse model overexpressing human PC7 led to ~45% higher circulating TG levels, whereas Afro-Americans expressing the human PC7 R504H variant had ~30% lower TG levels, suggesting that this substitution is a loss-of-function. However, the underlying mechanism of PCSK7 lipid regulation remains unclear. To establish the function of PC7 in TG metabolism, co-expression of PCSK7 and ApoA5 in hepatic cells led to reduced ApoA5 levels by cellular degradation, independently of the enzymatic activity of PCSK7. Furthermore, the direct interaction of PCSK7 and ApoA5 depends on the degree of phosphorylation at Ser505 (negative charge), and the presence of positively charged His-His183 doublet in ApoA5. Furthermore, we extended these cellular results to those in mice. Thus, PCSK7 KO mice fed a high fat diet revealed higher body fat (+50%) and larger adipocyte cells compared to wild type mice. In agreement, KO mice also exhibited ~30% higher ApoA5 circulating levels. We conclude that a PCSK7-inhibitor that prevents its interaction with ApoA5 may reduce plasma TG levels and possibly contribute to reduce hypertriglyceridemia in patients.