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Caffeine found to alter gene-expression of ‘bad cholesterol’ receptor PCSK9, new study finds

Why your caffeinated study habits might be good for more than just your grades.

Fig. 9, from article, Caffeine blocks PCSK9 expression and increases LDLc clearance in hepatocytes.

Coffee-consumers rejoice! A recent study conducted by researchers from McMaster University in Canada, published in Nature Communications, found that regular caffeine intake is linked to an increase in the removal of low-density lipoprotein (LDL) cholesterol, also known as ‘bad cholesterol,’ from the bloodstream. 

Found in all cells in the body, LDL cholesterol makes up the majority of bodily cholesterol, although it isn’t inherently ‘bad’ for us. In fact, we need it to survive; our liver produces it daily. However, excessive production (or consumption of high-LDL foods, such as meat and dairy) leads to build-up in our arteries. High levels in the bloodstream are responsible for an increased risk of heart disease and other coronary complications. 

High-density lipoprotein (HDL) is considered the ‘good’ cholesterol because it collects LDL from around the body, returning it to the liver, to be processed and removed from the body.

Working off pre-existing research, which affirms caffeine’s ability to reduce the risk of cardiovascular disease (CVD), the team from McMaster investigated two biochemical regulators responsible for regulating LDL cholesterol circulation in the bloodstream; low-density lipoprotein receptor (LDLR) and an enzyme called convertase subtilisin/kexin type 9 (PCSK9). They aimed to draw conclusions about the exact biological mechanisms and pathways which enable caffeine to reduce CVD risk. 

PCSK9 is a gene that dictates the number of LDL cholesterol receptors (LDLRs) on the surface of liver cells by breaking down LDLRs before they can reach the cell surface. LDL receptors play an integral role in the regulation of blood cholesterol levels. 

Critically, the McMaster researchers discovered that caffeine intake is able to reduce the levels of PCSK9 in the bloodstream. Tangibly, this leads to an increase in cholesterol receptor (LDLR) production on the surface of liver cells, providing the liver with more ‘hands’ to collect LDL cholesterol with. Ultimately, this causes an increased rate of cholesterol clearance from the bloodstream. 

This post-caffeination reduction in PCSK9 was found to operate mechanistically as follows: caffeine intake increases calcium ion levels in the endoplasmic reticulum (ER) of liver cells, which causes a block in the genetic transcription and activation of the protein SREBP2 — which regulates PCSK9 production. If SREBP2 is not produced, neither is PCSK9 and in turn, more cholesterol is removed from the bloodstream. 

The study’s senior author, Professor Richard Austin, explains that “two to three cups of coffee daily contains enough caffeine to trigger a cascade…” which instigates this blockage of PCSK9 regulation, boosting receptor production and cholesterol removal.  

“This discovery was completely unexpected and shows that ordinary food and drink have many more complex effects than we think.”

Highlighting the significance of their findings, Austin emphasises that “SREBP2 is implicated in a host of cardiometabolic diseases, such as diabetes and fatty liver disease, mitigating its function has far-reaching implications.” 

He concludes that calcium ions in the ER of liver cells are “a master regulator of cholesterol metabolism” and may provide a mechanistic biological pathway to reduce CVD risk.

Read the whole article in Nature Communications 13, 770 (2022) by P.F. Lebeau (et al).