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Udgivet

Aging suppresses sphingosine-1-phosphate chaperone ApoM in circulation resulting in maladaptive organ repair

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Vis graf over relationer

Here, we show that the liver-derived apolipoprotein M (ApoM) protects the lung and kidney from pro-fibrotic insults and that this circulating factor is attenuated in aged mice. Aged mouse hepatocytes exhibit transcriptional suppression of ApoM. This leads to reduced sphingosine-1-phosphate (S1P) signaling via the S1P receptor 1 (S1PR1) in the vascular endothelial cells of lung and kidney. Suboptimal S1PR1 angiocrine signaling causes reduced resistance to injury-induced vascular leak and leads to organ fibrosis. Plasma transfusion from Apom transgenic mice but not Apom knockout mice blocked fibrosis in the lung. Similarly, infusion of recombinant therapeutics, ApoM-Fc fusion protein enhanced kidney and lung regeneration and attenuated fibrosis in aged mouse after injury. Furthermore, we identified that aging alters Sirtuin-1-hepatic nuclear factor 4α circuit in hepatocytes to downregulate ApoM. These data reveal an integrative organ adaptation that involves circulating S1P chaperone ApoM+ high density lipoprotein (HDL), which signals via endothelial niche S1PR1 to spur regeneration over fibrosis.

OriginalsprogEngelsk
TidsskriftDevelopmental Cell
Vol/bind53
Udgave nummer6
Sider (fra-til)677-690
Antal sider14
ISSN1534-5807
DOI
StatusUdgivet - 22 jun. 2020

Bibliografisk note

Copyright © 2020 Elsevier Inc. All rights reserved.

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