Targeting Lysophosphatidic Acid Ameliorates Dyslipidemia in Familial Hypercholesterolemia

作者：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 · 发表于：Research · 年份：2025 · DOI：10.34133/research.0629 · 被引用次数：3 · 研究领域：Lipoproteins and Cardiovascular Health、Lipid metabolism and disorders、Diabetes, Cardiovascular Risks, and Lipoproteins

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 exa...