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The FoxOs are in the ApoM house
MacRae F Linton1,2, Patricia G Yancey1, Zoe M Leuthner1
1Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine and.
The Journal of Clinical Investigation
|April 1, 2022
Summary
Metabolic syndrome and insulin resistance lower protective HDL sphingosine-1-phosphate (S1P). Forkhead box O transcription factors regulate ApoM and S1P, offering potential therapeutic targets for metabolic disease and cardiovascular disease (CVD).
Area of Science:
- Cardiovascular Science
- Metabolic Science
- Molecular Biology
Background:
- Metabolic syndrome prevalence is rising globally, increasing cardiovascular disease (CVD) risk.
- Insulin resistance drives abnormal carbohydrate metabolism and dyslipidemia, contributing to CVD.
- Dysfunctional high-density lipoprotein (HDL) may increase CVD risk due to reduced HDL-associated sphingosine-1-phosphate (S1P).
Purpose of the Study:
- To investigate the link between insulin resistance, HDL-associated S1P, and the underlying regulatory mechanisms.
- To explore the role of Apolipoprotein M (ApoM) and forkhead box O (FoxO) transcription factors in this pathway.
Main Methods:
- Analysis of HDL-S1P levels in humans with insulin resistance.
- Assessment of ApoM levels in insulin-resistant mouse models (db/db mice).
- Utilized gain- and loss-of-function mouse models to determine the role of FoxO1, 3, and 4.
Main Results:
- HDL from insulin-resistant humans showed decreased S1P levels.
- ApoM, an S1P-binding protein on HDL, was reduced in insulin-resistant mice.
- FoxO transcription factors were identified as key regulators of both ApoM and HDL-S1P.
Conclusions:
- Insulin resistance is associated with reduced HDL-S1P, potentially mediated by decreased ApoM.
- FoxO transcription factors play a critical role in regulating ApoM and HDL-S1P levels.
- Targeting FoxO pathways may offer novel therapeutic strategies for metabolic abnormalities and CVD.
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