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Caffeine (CF) appears to lower the risk of Cardiovascular Disease (CVD). The process by which this occurs, however, has yet to be discovered. The influence of CF on the expression of two genuine regulators of circulating Low-density Lipoprotein Cholesterol (LDLc) levels, the Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and the Low-density Lipoprotein Receptor (LDLR), was studied in this study (LDLR). Following the discovery that CF decreased circulating PCSK9 levels while increasing hepatic LDLR expression, further CF-derived analogues with higher PCSK9 inhibitory potency than CF were created. The effect of CF on decreasing PCSK9 was later validated in a group of healthy individuals. We show that CF increases hepatic Endoplasmic Reticulum (ER) Ca2+ levels, which inhibits transcriptional activation of the Sterol Regulatory Element-binding Protein 2 (SREBP2), which regulates PCSK9, resulting in increased LDLR expression and LDLc clearance. Our findings reveal ER Ca2+ as a master regulator of cholesterol metabolism and a mechanism through which CF may protect against CVD.
Clinical Cardiology Journal received 12 citations as per Google Scholar report