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

Autor:	Obinata H; Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan obi@gunma-u.ac.jp Timothy.Hla@childrens.harvard.edu., Kuo A; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115., Wada Y; Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan., Swendeman S; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115., Liu CH; Weill Cornell Medical College, Cornell University, New York, NY 10065., Blaho VA; Weill Cornell Medical College, Cornell University, New York, NY 10065., Nagumo R; Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan., Satoh K; Shiga University Hikone, Shiga 522-8522, Japan., Izumi T; Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan., Hla T; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115 obi@gunma-u.ac.jp Timothy.Hla@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2019 Nov; Vol. 60 (11), pp. 1912-1921. Date of Electronic Publication: 2019 Aug 28.
DOI:	10.1194/jlr.RA119000277
Abstrakt:	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. (Copyright © 2019 Obinata et al.)
Databáze:	MEDLINE
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