Scientists have a new understanding of the protective effects of caffeine on the cardiovascular system. While its stimulant effects have long been characterized, a team of Canadian researchers have discovered how caffeine interacts with key cellular factors to remove cholesterol from the bloodstream.
On average, the habitual caffeine-consuming adult ingests 400 to 600 mg of caffeine daily – about two to three cups of coffee per day. Some recent population-level studies have shown that coffee and tea drinkers having that amount of caffeine have a reduced risk of death from cardiovascular disease, but a biochemical explanation of this phenomenon has long eluded researchers, until now.
In a landmark study, researchers have discovered that caffeine is responsible for triggering a cascade effect that ultimately reduces LDL cholesterol in the blood – the so-called "bad" cholesterol. High levels of LDL cholesterol are associated with increased risk of cardiovascular disease.
The study team was led by Richard Austin, Paul Lebeau, and Jae Hyun Byun of the Hamilton Centre for Kidney Research at The Research Institute of St. Joe's Hamilton.
They found that caffeine consumption was linked to a decrease in blood PCSK9 levels. PCSK9 is a protein that reduces the liver's ability to process excess LDL cholesterol. In the absence of PCSK9, more LDL cholesterol can be quickly removed from the bloodstream via the LDL receptor located on the surface of the liver.
These findings now provide the underlying mechanism by which caffeine and its derivatives can mitigate the levels of blood PCSK9 and thereby reduce the risk of cardiovascular disease."
Richard Austin, senior author of the study and professor, Department of Medicine, McMaster University
Specifically, caffeine and its derivatives were shown to block the activation of a protein called SREBP2, which otherwise increases liver PCSK9 expression and its transport into the bloodstream.
"Given that SREBP2 is implicated in a host of cardiometabolic diseases, such as diabetes and fatty liver disease, these findings may have far reaching implications," added Austin.
This molecular domino effect is similar to a phenomenon previously described by Austin and Lebeau. In 2021, they discovered how a rare genetic variant in the PCSK9 gene – one that reduces the secretion of PCSK9 from the liver – led to lower cholesterol levels and longer lifespans for those carrying this variant.
The study was published today in the journal Nature Communications.The interdisciplinary team included researchers from several McMaster University departments as well as the Libin Cardiovascular Institute of Alberta at the University of Calgary and the Clinical Research Institute of Montreal affiliated with the University of Montreal.
"These findings have wide ranging implications as they connect this widely consumed, biologically active compound to cholesterol metabolism at a molecular level," said co-author Guillaume Paré, who studies the genetics and molecular epidemiology of cardiovascular disease.
"This discovery was completely unexpected and shows that ordinary food and drink have many more complex effects than we think," said the McMaster professor of pathology and molecular medicine.
Working with study co-author and medicinal chemist Jakob Magolan, the team has developed novel caffeine derivatives that may lower blood levels of PCSK9 with much greater potency than caffeine, opening the possibility of developing new medicines to reduce LDL cholesterol.
"We are excited to be pursuing this new class of medicines – or nutraceuticals – for the potential treatment and prevention of cardiovascular disease," said Magolan, an associate professor of biochemistry and biomedical sciences at McMaster.
Researchers are also exploring additional health benefits of caffeine and its derivatives beyond those observed in the present study.
"It is exciting to see yet another potential clinical benefit from caffeine," said study co-author Mark Tarnopolsky, a McMaster professor of medicine who has previously shown that caffeine improved neuromuscular function.
"Coffee and tea drinkers have another important health reason to rejoice," said Austin, "minus the sugar!"
Lebeau, P.F., et al. (2022) Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance. Nature Communications. doi.org/10.1038/s41467-022-28240-9.