Department of Clinical Laboratory Medicine, The University of Tokyo.
Analytical Laboratory Chemistry, Graduate School of Health Care Sciences, Tokyo Medical and Dental University.
J Atheroscler Thromb. 2021 Jul 1;28(7):730-741. doi: 10.5551/jat.55699. Epub 2021 Jan 29.
Recently, it has been established that most of the pleiotropic effects of high-density lipoprotein (HDL) are attributed to sphingosine 1-phosphate (S1P), which rides on HDL via apolipoprotein M (ApoM). In subjects with diabetes mellitus, both the pleiotropic effects of HDL and its role in reverse cholesterol transport are reported to be impaired. To elucidate the mechanisms underlying the impaired pleiotropic effects of HDL in subjects with diabetes, from the aspects of S1P and ApoM.
The incubation of HDL in a high-glucose condition resulted in the dimerization of ApoM. Moreover, the treatment of HDL with methylglyoxal resulted in the modulation of the ApoM structure, as suggested by the results of western blot analysis, isoelectric focusing electrophoresis, and two-dimensional gel electrophoresis, which was reversed by treatment with anti-glycation reagents.
The glycation of HDL resulted in impaired binding of the glycated HDL to S1P, and the S1P on glycated HDL degraded faster. In the case of human subjects, on the other hand, although both the serum ApoM levels and the ApoM content in HDL were lower in subjects with diabetes, we did not observe the polymerization of ApoM.
Modulation of the quantity and quality of ApoM might explain, at least in part, the impaired functions of HDL in subjects with diabetes mellitus. ApoM might be a useful target for laboratory testing and/or the treatment of diabetes mellitus.
最近的研究表明，高密度脂蛋白（HDL）的大多数多效性作用归因于鞘氨醇 1-磷酸（S1P），它通过载脂蛋白 M（ApoM）与 HDL 结合。在糖尿病患者中，HDL 的多效性作用及其在胆固醇逆向转运中的作用均被报道受损。为了阐明糖尿病患者 HDL 多效性作用受损的机制，从 S1P 和 ApoM 两个方面进行了研究。
在高葡萄糖条件下孵育 HDL 会导致 ApoM 二聚化。此外，用甲基乙二醛处理 HDL 会导致 ApoM 结构发生变化，如 Western blot 分析、等电聚焦电泳和二维凝胶电泳的结果所示，用抗糖基化试剂处理可以逆转这种变化。
HDL 的糖基化导致糖基化 HDL 与 S1P 的结合受损，糖基化 HDL 上的 S1P 降解更快。另一方面，在人类受试者中，尽管糖尿病患者的血清 ApoM 水平和 HDL 中的 ApoM 含量较低，但我们没有观察到 ApoM 的聚合。
ApoM 数量和质量的调节至少可以部分解释糖尿病患者 HDL 功能受损的原因。ApoM 可能是实验室检测和/或糖尿病治疗的有用靶点。
