Grant: Project Grant

There is accumulating clinical evidence that caffeine, one of the most highly consumed naturally occurring drugs found in coffee and tea, reduces the risk of all cause mortality, including metabolic diseases. The average adult consumes between 400 and 600 mg/day of caffeine and organizations like Health Canada and the Food and Drug Administration conclude that such doses are not negatively associated with toxicity, heart effects, bone status, or incidence of cancer. On the contrary, accumulating evidence now suggests that moderate to high levels of caffeine, consumed daily in the form of non-alcoholic beverages, are associated with a protective effect against a wide range of metabolic diseases, including diabetes and dyslipidemia. We have for the first time explained how caffeine protects against the accumulation of blood lipids. In the liver, caffeine is able to reduce the activity of cellular factors, termed sterol regulatory-element binding proteins (SREBPs), which are responsible for increasing the synthesis of cholesterol and triglycerides, lipids which contribute to atherosclerosis, the underlying cause of heart disease. Specifically, this inhibition of the SREBPs also reduces blood levels of PCSK9, which further reduces blood cholesterol. We have now developed a wide range of novel caffeine derivatives that have greater potency in blocking SREBP activation and reducing blood PCSK9 and lipid levels. Based on our findings, we predict that these caffeine derivatives represent new medicines for the treatment of metabolic disturbances, including diabetes, obesity and fatty liver disease that culminates in life threatening heart disease.