HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular S1P signaling functions in the vascular and immune systems. We previously showed that ApoM- and albumin-bound S1P exhibit differences in receptor activation and biological functions. Whether the physiological functions of S1P require chaperones is not clear. We examined ApoM-deficient, albumin-deficient, and double-KO (DKO) mice for circulatory S1P and its biological functions. In albumin-deficient mice, ApoM was upregulated, thus enabling S1P functions in embryonic development and postnatal adult life. The Apom:Alb DKO mice reproduced, were viable, and exhibited largely normal vascular and immune functions, which suggested sufficient extracellular S1P signaling. However, Apom:Alb DKO mice had reduced levels (∼25%) of plasma S1P, suggesting that novel S1P chaperones exist to mediate S1P functions. In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner.

中文翻译：

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在ApoM和白蛋白缺乏的小鼠中鉴定ApoA4为鞘氨醇1-磷酸伴侣。

HDL结合的ApoM和白蛋白是循环生物活性脂质鞘氨醇1-磷酸（S1P）的蛋白伴侣。在这种作用下，它们支持血管和免疫系统中重要的细胞外S1P信号传导功能。我们先前显示，ApoM和白蛋白结合的S1P在受体激活和生物学功能上表现出差异。S1P的生理功能是否需要伴侣。我们检查了ApoM缺陷，白蛋白缺陷和双KO（DKO）小鼠的循环S1P及其生物学功能。在缺乏白蛋白的小鼠中，ApoM被上调，从而使S1P在胚胎发育和产后成年生活中发挥功能。该APOM：白蛋白DKO小鼠繁殖，存活，并表现出很大程度上正常的血管和免疫功能，这表明足够的细胞外S1P信号传导。然而，Apom：Alb DKO小鼠的血浆S1P水平降低（约25％），表明存在新型S1P分子伴侣来介导S1P功能。在这项研究中，我们报告了ApoA4作为一种新型的S1P结合蛋白的鉴定。重组ApoA4与S1P结合，激活了多个S1P受体，并促进了血管内皮屏障功能，这在没有ApoM和白蛋白的情况下均能反映其作为S1P分子伴侣的功能。我们建议，多个S1P伴侣进化以冗余的方式支持这种溶血脂介体的复杂和必要的细胞外信号传导功能。