Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

• Published in: Journal of lipid research 2019-11, Vol.60 (11), p.1912-1921
• Main Authors: Obinata, Hideru, Kuo, Andrew, Wada, Yukata, Swendeman, Steven, Liu, Catherine H., Blaho, Victoria A., Nagumo, Rieko, Satoh, Kenichi, Izumi, Takashi, Hla, Timothy
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; apolipoprotein A4; apolipoprotein M; apolipoproteins; Apolipoproteins A - chemistry; Apolipoproteins A - metabolism; Apolipoproteins M - deficiency; Apolipoproteins M - genetics; Gene Knockout Techniques; high density lipoprotein; lipid transport; lysophospholipid; Lysophospholipids - metabolism; Mice; Mice, Inbred C57BL; Serum Albumin - deficiency; Sphingosine - analogs & derivatives; Sphingosine - metabolism; sphingosine 1-phosphate receptors; Sphingosine-1-Phosphate Receptors - metabolism
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.RA119000277

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.