Aging Suppresses Sphingosine-1-Phosphate Chaperone ApoM in Circulation Resulting in Maladaptive Organ Repair

Area of Science:

• Biochemistry
• Vascular Biology
• Aging Research

Background:

• Liver-derived apolipoprotein M (ApoM) is a circulating factor.
• ApoM influences sphingosine-1-phosphate (S1P) signaling.
• Aging is associated with organ dysfunction and fibrosis.

Purpose of the Study:

• To investigate the role of ApoM in protecting lung and kidney from fibrosis.
• To determine the impact of aging on ApoM levels and function.
• To explore therapeutic strategies involving ApoM to prevent or treat organ fibrosis.

Main Methods:

• Investigated ApoM expression in aged mice hepatocytes.
• Analyzed sphingosine-1-phosphate (S1P) signaling via S1P receptor 1 (S1PR1) in lung and kidney vasculature.
• Utilized plasma transfusion from ApoM transgenic and knockout mice.
• Administered recombinant ApoM-Fc fusion protein in aged mice.
• Examined the Sirtuin-1-hepatic nuclear factor 4α circuit in hepatocytes.

Main Results:

• Aged mice showed reduced ApoM levels due to transcriptional suppression in hepatocytes.
• Lower ApoM led to impaired S1P/S1PR1 signaling, increasing vascular leak and organ fibrosis.
• Plasma transfusion from ApoM-overexpressing mice blocked lung fibrosis.
• ApoM-Fc fusion protein treatment attenuated fibrosis and enhanced regeneration in aged mice.
• Aging disrupts the Sirtuin-1-hepatic nuclear factor 4α pathway, downregulating ApoM.

Conclusions:

• Circulating ApoM, chaperoned by HDL, is crucial for protecting lung and kidney from fibrosis.
• Impaired ApoM-S1P-S1PR1 axis signaling in aging contributes to organ damage.
• ApoM-based therapies hold promise for treating age-related organ fibrosis and promoting regeneration.