Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine and.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
J Clin Invest. 2022 Apr 1;132(7). doi: 10.1172/JCI158471.
The prevalence of metabolic syndrome continues to increase globally and heightens the risk for cardiovascular disease (CVD). Insulin resistance is a core pathophysiologic mechanism that causes abnormal carbohydrate metabolism and atherogenic changes in circulating lipoprotein quantity and function. In particular, dysfunctional HDL is postulated to contribute to CVD risk in part via loss of HDL-associated sphingosine-1-phosphate (S1P). In this issue of the JCI, Izquierdo et al. demonstrate that HDL from humans with insulin resistance contained lower levels of S1P. Apolipoprotein M (ApoM), a protein constituent of HDL that binds S1P and controls bioavailability was decreased in insulin-resistant db/db mice. Gain- and loss-of-function mouse models implicated the forkhead box O transcription factors (FoxO1,3,4) in the regulation of both ApoM and HDL-associated S1P. These data have important implications for potential FoxO-based therapies designed to treat lipid and carbohydrate abnormalities associated with human metabolic disease and CVD.
代谢综合征的患病率在全球范围内持续上升，增加了心血管疾病（CVD）的风险。胰岛素抵抗是导致异常碳水化合物代谢和循环脂蛋白数量和功能致动脉粥样变化的核心病理生理机制。特别是，功能失调的高密度脂蛋白（HDL）被认为通过丧失与 HDL 相关的鞘氨醇-1-磷酸（S1P）而部分导致 CVD 风险增加。在本期 JCI 中，Izquierdo 等人证明，来自胰岛素抵抗患者的 HDL 中 S1P 水平较低。载脂蛋白 M（ApoM）是 HDL 的一种蛋白质成分，可结合 S1P 并控制其生物利用度，在胰岛素抵抗的 db/db 小鼠中降低。获得和丧失功能的小鼠模型表明叉头框 O 转录因子（FoxO1、3、4）参与调节 ApoM 和与 HDL 相关的 S1P。这些数据对于基于 FoxO 的潜在治疗方法具有重要意义，旨在治疗与人类代谢疾病和 CVD 相关的脂质和碳水化合物异常。
