State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Pharm Biomed Anal. 2024 Mar 15;240:115933. doi: 10.1016/j.jpba.2023.115933. Epub 2023 Dec 23.
Hyperlipidemia is a global metabolic disorder characterized by dysregulation of lipid metabolism. This dysregulation is closely associated with the altered homeostasis of cholesterol-cholesteryl ester (CE) metabolism in systemic circulation, and some organs. Additionally, the relationship between oxidized cholesteryl ester (oxCE) and the disease has also gained attention. Currently, there is a lack of comprehensive research on the alterations in cholesterol-CE metabolism in the context of hyperlipidemia, as well as the characteristics of lipid-lowering agents in regulating this metabolic state. Therefore, 40 oxCEs were identified in the hamster liver sample, and novel ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) methods were established for simultaneous analysis of cholesterol, 57 CEs, and 40 oxCEs in the serum, liver, adipose tissue, and intestine of hyperlipidemic hamsters. This study investigated the metabolic alterations between cholesterol-CE/oxCE in hyperlipidemic hamsters and those treated with lipid-lowering agents, including the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe and the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor avasimibe. The study findings demonstrate metabolic disorders in cholesterol-CE/oxCE homeostasis in hyperlipidemic hamsters. Lipid-lowering agent therapy can improve the metabolic dysregulation caused by hyperlipidemia, with distinct characteristics: ezetimibe is more effective in reducing cholesterol, while avasimibe is more effective in reducing CEs/oxCEs. Eight potential biomarkers indicating the dysregulation of cholesterol-CE metabolism caused by hyperlipidemia and its improvement by lipid-lowering agents have been identified in the serum. This study offers new insights into the hyperlipidemia pathophysiology and the mechanisms of lipid-lowering agents from a novel perspective on cholesterol-CE/oxCE metabolic homeostasis.
高脂血症是一种全球性的代谢紊乱，其特征是脂质代谢失调。这种失调与胆固醇-胆固醇酯（CE）代谢在全身循环和一些器官中的内稳态改变密切相关。此外，氧化胆固醇酯（oxCE）与疾病的关系也引起了关注。目前，关于高脂血症背景下胆固醇-CE 代谢的改变以及降脂药物调节这种代谢状态的特点，缺乏全面的研究。因此，在仓鼠肝脏样本中鉴定出 40 种 oxCE，并建立了新型的超高效液相色谱-串联质谱（UHPLC-MS/MS）方法，用于同时分析高脂血症仓鼠血清、肝脏、脂肪组织和肠道中的胆固醇、57 种 CE 和 40 种 oxCE。本研究调查了高脂血症仓鼠和用降脂药物治疗的仓鼠之间胆固醇-CE/oxCE 代谢的改变，包括 NPC1L1 抑制剂依折麦布（ezetimibe）和酰基辅酶 A：胆固醇酰基转移酶（ACAT）抑制剂阿伐麦布（avasimibe）。研究结果表明，高脂血症仓鼠的胆固醇-CE/oxCE 内稳态存在代谢紊乱。降脂药物治疗可以改善高脂血症引起的代谢失调，具有明显的特征：依折麦布更有效地降低胆固醇，而阿伐麦布更有效地降低 CE/oxCE。在血清中鉴定出 8 种潜在的生物标志物，这些标志物表明高脂血症引起的胆固醇-CE 代谢失调及其通过降脂药物得到改善。本研究从胆固醇-CE/oxCE 代谢内稳态的新视角为高脂血症的病理生理学和降脂药物的作用机制提供了新的见解。
