Scientists discover how caffeine protects against cardiovascular disease

Scientists discover how caffeine protects against cardiovascular disease
A The effect of caffeine (CF; 200 µM) on SREBP2 and SREBP1 mRNA expression was examined in primary mouse hepatocytes (PMH) in the presence and absence of thapsigargin (TG; 100 nM), an established activator of SREBPs. The downstream product of SREBP2 transcriptional activity, HMGR, was also examined. B, C The inhibitory effect of CF on SREBP2 was also examined in primary human hepatocytes (PHH) and HepG2 cells. D CF-mediated SREBP1 inhibition was also examined in PMH (*p < 0.05). E–G HuH7 cells were transfected with a reporter construct encoding a sterol-regulatory element-driven green fluorescent protein (SRE-GFP; green color). Cells were subsequently treated with CF (200 µM) and/or TG (100 nM) 24 h later. GFP and nuclear (n)SREBP2 expression were examined via immunoblot analysis. GFP expression was also assessed via immunofluorescent staining, which was quantified using ImageJ. H The cellular localization of SREBP2 (green color) in CF- and TG-treated HuH7 cells was also examined via immunofluorescent staining. Nuclei containing activated SREBP2 are indicated by white arrows. For all data in this figure, n = 5 biologically independent samples per group; data presented are mean ± s.d). Scale bars; G 100 µm; H 20 µm. Statistical comparisons between two groups were conducted using unpaired two-tailed Student’s t-tests, while comparisons between multiple groups were compared using one-way ANOVAs with the Tukey HSD post-hoc test (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). Credit: DOI: 10.1038/s41467-022-28240-9

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 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 and Paul Lebeau 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," said Austin, senior author of the study and professor in the Department of Medicine at 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 , 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 .

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 ," 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 improved neuromuscular function.

More information: Paul F. Lebeau et al, Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance, Nature Communications (2022). DOI: 10.1038/s41467-022-28240-9
Journal information: Nature Communications

Citation: Scientists discover how caffeine protects against cardiovascular disease (2022, February 16) retrieved 7 December 2022 from
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