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)和低密度脂蛋白受体(LDLR), was studied in this study (LDLR). Following the discovery that CF decreased circulatingPCSK9levels while increasing hepatic LDLR expression, further CF-derived analogues with higherPCSK9inhibitory potency than CF were created. The effect of CF on decreasingPCSK9was 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.
