Natural phytochemicals as small-molecule proprotein convertase subtilisin/kexin type 9 inhibitors.

IF 1.4 Q2 MEDICINE, GENERAL & INTERNAL Tzu Chi Medical Journal Pub Date : 2024-09-05 eCollection Date: 2024-10-01 DOI:10.4103/tcmj.tcmj_46_24
Je-Wen Liou, Pei-Yi Chen, Wan-Yun Gao, Jui-Hung Yen
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Abstract

A decrease in the levels of low-density lipoprotein receptors (LDLRs) leads to the accumulation of LDL cholesterol (LDL-C) in the bloodstream, resulting in hypercholesterolemia and atherosclerotic cardiovascular diseases. Increasing the expression level or inducing the activity of LDLR in hepatocytes can effectively control hypercholesterolemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, primarily produced in the liver, promotes the degradation of LDLR. Inhibiting the expression and/or function of PCSK9 can increase the levels of LDLR on the surface of hepatocytes and promote LDL-C clearance from the plasma. Thus, targeting PCSK9 represents a new strategy for developing preventive and therapeutic interventions for hypercholesterolemia. Currently, monoclonal antibodies are used as PCSK9 inhibitors in clinical practice. However, the need for oral and affordable anti-PCSK9 medications limits the perspective of choosing PCSK9 inhibitors for clinical usage. Emerging research reports have demonstrated that natural phytochemicals have efficacy in maintaining cholesterol stability and regulating lipid metabolism. Developing novel natural phytochemical PCSK9 inhibitors can serve as a starting point for developing small-molecule drugs to reduce plasma LDL-C levels in patients. In this review, we summarize the current literature on the critical role of PCSK9 in controlling LDLR degradation and hypercholesterolemia, and we discuss the results of studies attempting to develop PCSK9 inhibitors, with an emphasis on the inhibitory effects of natural phytochemicals on PCSK9. Furthermore, we provide insight into the mechanisms of action by which the reported phytochemicals exert their potential PCSK9 inhibitory effects against hypercholesterolemia.

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天然植物化学物质作为小分子蛋白转化酶枯草酶/kexin 9 型抑制剂。
低密度脂蛋白受体(LDLR)水平下降会导致低密度脂蛋白胆固醇(LDL-C)在血液中积累,从而引起高胆固醇血症和动脉粥样硬化性心血管疾病。提高肝细胞中 LDLR 的表达水平或诱导其活性可有效控制高胆固醇血症。Proprotein convertase subtilisin/kexin type 9(PCSK9)蛋白主要产生于肝脏,可促进 LDLR 的降解。抑制 PCSK9 的表达和/或功能可提高肝细胞表面的 LDLR 水平,促进血浆中 LDL-C 的清除。因此,靶向 PCSK9 是开发高胆固醇血症预防和治疗干预措施的新策略。目前,临床上使用单克隆抗体作为 PCSK9 抑制剂。然而,由于需要口服且价格低廉的抗 PCSK9 药物,限制了临床使用 PCSK9 抑制剂的选择范围。新的研究报告表明,天然植物化学物质具有维持胆固醇稳定性和调节脂质代谢的功效。开发新型天然植物化学 PCSK9 抑制剂可作为开发小分子药物的起点,以降低患者的血浆 LDL-C 水平。在这篇综述中,我们总结了目前有关 PCSK9 在控制 LDLR 降解和高胆固醇血症中的关键作用的文献,并讨论了试图开发 PCSK9 抑制剂的研究结果,重点是天然植物化学物质对 PCSK9 的抑制作用。此外,我们还深入探讨了所报道的植物化学物质对高胆固醇血症产生潜在 PCSK9 抑制作用的作用机制。
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来源期刊
Tzu Chi Medical Journal
Tzu Chi Medical Journal MEDICINE, GENERAL & INTERNAL-
CiteScore
3.40
自引率
0.00%
发文量
44
审稿时长
13 weeks
期刊介绍: The Tzu Chi Medical Journal is the peer-reviewed publication of the Buddhist Compassion Relief Tzu Chi Foundation, and includes original research papers on clinical medicine and basic science, case reports, clinical pathological pages, and review articles.
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