Evidence suggests that caffeine reduces cardiovascular disease risk. However, the mechanism by which this occurs is still unknown. In a new study, researchers from McMaster University and elsewhere investigated the effect of caffeine on the expression of two regulators of circulating low-density lipoprotein (LDL) cholesterol — or ‘bad’ cholesterol — levels.
Caffeine blocks PCSK9 expression and increases LDL cholesterol clearance in hepatocytes. Image credit: Sci-News.com.
“Just two to three average-sized cups of coffee per day contains enough caffeine to trigger a cascade effect, which reduces the levels of LDL cholesterol,” said McMaster University’s Professor Richard Austin, senior author of the study.
“High bloodstream levels of LDL cholesterol are associated with an increased risk of cardiovascular disease.”
“Regular caffeine consumption is linked to reduced blood levels of the PCSK9 protein, which increases the liver’s ability to remove excess LDL cholesterol from the bloodstream.”
“Coffee and tea drinkers have another important health reason to rejoice — minus the sugar,” he added.
“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.”
The treatment of liver hepatocytes with caffeine increases the concentration of ER Ca2+: excess ER Ca2+ leads to an increase in the peptide binding capacity and chaperone activity of ER-resident GRP78; the result is an ER-resident GRP78-SREBP2 complex with enhanced stability; the failure of SREBP2 to quickly exit the ER leads to a net reduction in expression of lipid regulatory genes, including PCSK9, SREBP2 and PCSK9; with reduced outflow of de novo PCSK9, cell-surface LDLR exhibits increased half-life and abundance, leading in a net increase in LDL cholesterol clearance. Image credit: Lebeau et al., doi: 10.1038/s41467-022-28240-9.
Caffeine and its derivatives can also block the activation of a protein called SREBP2, which in turn reduces the levels of PCSK9 into the bloodstream.
“Given that SREBP2 is implicated in a host of cardiometabolic diseases, such as diabetes and fatty liver disease, mitigating its function has far reaching implications,” Professor Austin said.
“Recent population-level studies have shown that coffee and tea drinkers have a reduced risk of death from cardiovascular disease, but a biochemical explanation of this phenomenon has previously eluded researchers,” he added.
“These findings have wide ranging implications as they connect this widely consumed, biologically active compound to cholesterol metabolism at a molecular level,” said McMaster University’s Professor Guillaume Paré, co-author of the study.
“This discovery was completely unexpected and shows that ordinary food and drink have many more complex effects than we think.”
The authors also developed new caffeine derivatives that potently lower blood PCSK9 levels, potentially leading to new LDL cholesterol treatments.
“We are excited to be pursuing this new class of medicines — or nutraceuticals — for the potential treatment and prevention of cardiovascular disease,” said Dr. Jakob Magolan, also from McMaster University.
“It is exciting to see yet another potential clinical benefit from caffeine,” added McMaster University’s Professor Mark Tarnopolsky.
The findings are published in the journal Nature Communications.
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P.F. Lebeau et al. 2022. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance. Nat Commun 13, 770; doi: 10.1038/s41467-022-28240-9
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