Can Caffeine be the Key to Fighting CVD, Lowering LDL Cholesterol?

Via Peters

Author: Amanda Roberts, PharmD Candidate, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences Institute of Public Health

Studies have found that average levels of moderate caffeine intake are related to lower cardiovascular (CVD) risk.

Caffeine is a central nervous system stimulant commonly found in coffee, tea, and sodas. The average adult coffee drinker has about 400 – 600 mg of caffeine daily. Studies have shown that moderate to high levels (>600 mg) of caffeine consumed daily are connected to a reduction in cardiovascular disease (CVD) risk. CVD is highly correlated to elevated levels of low–density lipoprotein cholesterol (LDLc). A study demonstrated that caffeine suppresses LDLc regulators and regulatory genes.

PCSK9 improves the degradation of the LDLR and reduces the ability of hepatocytes to bind with LDLc. Thus, caffeine’s impact on PCSK9 expression and secretion in hepatocytes was evaluated. Hepatocytes that express and secrete PCSK9 cells, in addition to primary mouse – and human – hepatocytes, were treated with caffeine for 24 hours. They were then assessed for PCSK9 expression. This assessment was performed using immunoblots and real-time PCR. Additional analysis was done by treating HepG2 cells with an elevating dose of caffeine. The study also assessed the effect of caffeine on TG – induced SREBP2 activation, which is involved in the transcriptional regulation of PCSK9. The impact on the uptake of hepatic LDL was also assessed. An assay was also performed in mice. For 12 weeks, PCSK9 positive and PSCK9 negative mice were treated with either caffeine or PBS – a vehicle for 8 hours and Dil – LDL for 1 hour before sacrifice. Caffeine’s ability to impact PCSK9 levels in fasted healthy volunteers was also studied. Patients were ages 22 – 45 and underwent fasting for 12 hours before the oral administration of caffeine. Caffeine treatment was given 400 mg orally, or approximately 5 mg/kg. Blood serum was collected before caffeine treatment, 2 hours after treatment, and 4 hours after treatment. The statistical comparisons that were made between the two groups were made using unpaired Student’s t-tests. Comparisons made between multiple groups were made using one–way ANOVAs with the Tukey HSD post – hoc test. The paired Student’s t-test was used to compare human subjects’ pre – and post-treatment values. Differences amongst the groups were significant at p <0.05, and values were expressed as mean +/- s.d.

When evaluating caffeine’s impact on PCSK9, caffeine reduced protein and mRNA transcript levels of PCSK9. When HepG2 was treated with an elevating dose of caffeine, PCSK9 showed a great response to caffeine from the 10² to the 10⁸ nM range in hepatocytes. Additionally, it was found that caffeine blocked the expression of SREBP2 activation in PMHs, PHHs, and HepG2 cells. Furthermore, caffeine increased LDLc uptake, and U18, an agent that increases PCSK levels, reduced LDLc uptake. In the mice analysis, caffeine increased hepatic cell surface LDLR expression in PCSK9 positive mice but not in PSCK9 negative mice. Finally, in the analysis of healthy volunteers, caffeine reduced plasma PCSK9 levels in patients by 25% and 21% 2 hours and 4 hours after treatment, respectively.

The study’s data shows that caffeine can significantly reduce PCSK9 expression in many hepatocyte cell models. Caffeine was also able to show that it blocked SREBP expression. Given that SREBP2 has a clearly defined role in the transcriptional regulation of PCSK9, the data supports that caffeine reduced PCSK9 expression and secretion. SREBP2 also plays a role in the expression of HMGR; therefore, it may be possible that caffeine also reduces LDLc levels through the blocking of HBGR  – mediated cholesterol synthesis. The data also proved that caffeine increases hepatic LDLc clearance through the increased expression of LDLR, which is dependent on its blocking of PCSK9 secretion from hepatocytes. PCSK9 leads to the onset and further development of cardiovascular disease. It is thus one of the most costly current health care problems.

Further understanding of the regulatory processes that modify the expression and secretion of PCSK9 may lead to the development of anti – PCSK9 treatment methods. In addition, methods may develop that are not as expensive as the current treatment options. Thus, this study provides data that shows that caffeine can be a starting point in creating treatments that lower cardiovascular risk.

Practice Pearls:

  • Caffeine can reduce the levels of LDL cholesterol in the blood.
  • Frequent caffeine intake can lead to a decreased risk of cardiovascular disease.
  • The findings of this study may lead to a new class of medications that are the most cost-effective for the treatment and prevention of cardiovascular disease.


References for “Can Caffeine be the Key to Fighting CVD?”:
Lebeau, P.F., Byun, J.H., Platko, K. et al. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance. Nat Commun 13, 770 (2022).

McMaster University. Scientists have discovered how caffeine protects against cardiovascular disease. Medical Xpress . Published February 16, 2022. Accessed February 24, 2022..


Amanda Roberts, PharmD Candidate, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences Institute of Public Health

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