Aging Suppresses Sphingosine-1-Phosphate Chaperone ApoM in Circulation Resulting in Maladaptive Organ Repair
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Developmental Cell |
Volume | 53 |
Issue number | 6 |
Pages (from-to) | 677-690 |
ISSN | 1534-5807 |
DOIs | |
Publication status | Published - 2020 |
- aging, endothelial cell, fibrosis, kidney repair, lipoprotein, lung regeneration, sphingosine-1-phosphate receptor, vascular barrier, vascular niche
Research areas
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607448/pdf/nihms-1638874.pdf
Accepted author manuscript
ID: 244527597