咖啡因阻断srebp2诱导的肝脏PCSK9表达,增强ldlr介导的胆固醇清除。

IF 3.784 3区 化学 Q1 Chemistry
Paul F Lebeau, Jae Hyun Byun, Khrystyna Platko, Paul Saliba, Matthew Sguazzin, Melissa E MacDonald, Guillaume Paré, Gregory R Steinberg, Luke J Janssen, Suleiman A Igdoura, Mark A Tarnopolsky, S R Wayne Chen, Nabil G Seidah, Jakob Magolan, Richard C Austin
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引用次数: 35

摘要

有证据表明咖啡因(CF)可以降低心血管疾病(CVD)的风险。然而,发生这种情况的机制尚未被揭示。在这里,我们研究了CF对循环低密度脂蛋白胆固醇(LDLc)水平的两种真正调节因子表达的影响;蛋白转化酶枯草杆菌素/酮素9型(PCSK9)和低密度脂蛋白受体(LDLR)。在观察到CF降低循环PCSK9水平和增加肝脏LDLR表达后,研究人员开发了其他CF衍生的类似物,与CF本身相比,它们对PCSK9的抑制作用更强。CF降低pcsk9的作用随后在一组健康志愿者中得到证实。在机制上,我们证明了CF增加肝内质网(ER) Ca2+水平,以阻断负责调节PCSK9的固醇调节元件结合蛋白2 (SREBP2)的转录激活,从而增加LDLR的表达和LDLc的清除。我们的研究结果强调了ER Ca2+作为胆固醇代谢的主要调节因子,并确定了CF可能预防CVD的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.

Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance.

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.

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来源期刊
ACS Combinatorial Science
ACS Combinatorial Science CHEMISTRY, APPLIED-CHEMISTRY, MEDICINAL
自引率
0.00%
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0
审稿时长
1 months
期刊介绍: The Journal of Combinatorial Chemistry has been relaunched as ACS Combinatorial Science under the leadership of new Editor-in-Chief M.G. Finn of The Scripps Research Institute. The journal features an expanded scope and will build upon the legacy of the Journal of Combinatorial Chemistry, a highly cited leader in the field.
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