Targeting Lysophosphatidic Acid Ameliorates Dyslipidemia in Familial Hypercholesterolemia.

IF 11 1区 综合性期刊 Q1 Multidisciplinary
Research Pub Date : 2023-02-27 eCollection Date: 2025-01-01 DOI:10.34133/research.0629
Zhiyong Du, Yu Wang, Fan Li, Xuechun Sun, Yunhui Du, Linyi Li, Huahui Yu, Chaowei Hu, Haili Sun, Xiaoqian Gao, Lijie Han, Zihan Zhang, Jingci Xing, Luya Wang, Jianping Li, Yanwen Qin
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引用次数: 0

Abstract

Familial hypercholesterolemia (FH) is a lipoprotein disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature atherosclerotic cardiovascular disease. Recent evidences have shown that several glycerophospholipid species were markedly altered in experimental FH animals and exhibited diverse bioactivities. Nevertheless, the glycerophospholipid profiles and their associated biological implications in human FH remain largely unknown. In this study, we sought to comprehensively delineate the glycerophospholipid phenotypes in human FH and to investigate the functional roles of key FH-altered glycerophospholipid molecules on cholesterol metabolism. Targeted analysis of 328 glycerophospholipid metabolites was used to profile the differentiated alterations in patients with homozygous FH (HoFH; n = 181), heterozygous FH (HeFH; n = 452), and non-FH hypercholesterolemia (n = 382). Our findings revealed that the glycerophospholipid phenotypes of FH and non-FH hypercholesterolemia were dominated by a spectrum of metabolites involved in the lysophosphatidic acid (LPA) metabolism. Among the LPA features, palmitoyl-LPA (16:0) showed significant association with the clinical levels of LDL-C and total cholesterol in HoFH and HeFH populations. Using functional metabolomic strategy and murine FH model, we demonstrated that supplementation with LPA 16:0 elevated the plasma levels of LDL and free/esterified cholesterol and exacerbated the atherosclerotic lesions. Conversely, inhibition of autotaxin-mediated LPA 16:0 production significantly ameliorated dyslipidemia. Mechanistically, we uncovered that LPA 16:0 could disrupt hepatic cholesterol homeostasis by impairing cholesterol excretion and inhibiting primary bile acid synthesis. In summary, our study offers novel insights into lipid metabolism in human FH and posits that targeting LPA metabolism may represent a promising therapeutic strategy for reducing cholesterol levels in the FH population.

靶向溶血磷脂酸可改善家族性高胆固醇血症的血脂异常。
家族性高胆固醇血症(FH)是一种以血浆低密度脂蛋白胆固醇(LDL-C)水平升高和过早动脉粥样硬化性心血管疾病风险增加为特征的脂蛋白疾病。最近的证据表明,几种甘油磷脂种类在实验FH动物中发生了显着变化,并表现出多种生物活性。然而,甘油磷脂谱及其在人类FH中的相关生物学意义在很大程度上仍然未知。在这项研究中,我们试图全面描述人类FH中的甘油磷脂表型,并研究关键的FH改变的甘油磷脂分子在胆固醇代谢中的功能作用。利用328种甘油磷脂代谢物的靶向分析来描述纯合子FH (HoFH;n = 181),杂合FH (HeFH;n = 452)和非fh型高胆固醇血症(n = 382)。我们的研究结果表明,FH和非FH高胆固醇血症的甘油磷脂表型由参与溶血磷脂酸(LPA)代谢的代谢物谱主导。在LPA特征中,棕榈酰LPA(16:0)与HoFH和HeFH人群的临床LDL-C和总胆固醇水平显著相关。通过功能代谢组学策略和小鼠FH模型,我们证明补充LPA 16:0可提高血浆LDL和游离/酯化胆固醇水平,并加剧动脉粥样硬化病变。相反,抑制自taxin介导的LPA 16:0的产生可显著改善血脂异常。在机制上,我们发现LPA 16:0可以通过损害胆固醇排泄和抑制初级胆汁酸合成来破坏肝脏胆固醇稳态。总之,我们的研究为人类FH中的脂质代谢提供了新的见解,并假设靶向LPA代谢可能代表了降低FH人群胆固醇水平的有希望的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Research
Research Multidisciplinary-Multidisciplinary
CiteScore
13.40
自引率
3.60%
发文量
0
审稿时长
14 weeks
期刊介绍: Research serves as a global platform for academic exchange, collaboration, and technological advancements. This journal welcomes high-quality research contributions from any domain, with open arms to authors from around the globe. Comprising fundamental research in the life and physical sciences, Research also highlights significant findings and issues in engineering and applied science. The journal proudly features original research articles, reviews, perspectives, and editorials, fostering a diverse and dynamic scholarly environment.
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