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Citations to this article

Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway
María Concepción Izquierdo, … , Barry E. Hurwitz, Rebecca A. Haeusler
María Concepción Izquierdo, … , Barry E. Hurwitz, Rebecca A. Haeusler
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(7):e146219. https://doi.org/10.1172/JCI146219.
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Research Article Metabolism Article has an altmetric score of 27

Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway

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Abstract

Multiple beneficial cardiovascular effects of HDL depend on sphingosine-1-phosphate (S1P). S1P associates with HDL by binding to apolipoprotein M (ApoM). Insulin resistance is a major driver of dyslipidemia and cardiovascular risk. However, the mechanisms linking alterations in insulin signaling with plasma lipoprotein metabolism are incompletely understood. The insulin-repressible FoxO transcription factors mediate key effects of hepatic insulin action on glucose and lipoprotein metabolism. This work tested whether hepatic insulin signaling regulates HDL-S1P and aimed to identify the underlying molecular mechanisms. We report that insulin-resistant, nondiabetic individuals had decreased HDL-S1P levels, but no change in total plasma S1P. This also occurred in insulin-resistant db/db mice, which had low ApoM and a specific reduction of S1P in the HDL fraction, with no change in total plasma S1P levels. Using mice lacking hepatic FoxOs (L-FoxO1,3,4), we found that hepatic FoxOs were required for ApoM expression. Total plasma S1P levels were similar to those in controls, but S1P was nearly absent from HDL and was instead increased in the lipoprotein-depleted plasma fraction. This phenotype was restored to normal by rescuing ApoM in L-FoxO1,3,4 mice. Our findings show that insulin resistance in humans and mice is associated with decreased HDL-associated S1P. Our study shows that hepatic FoxO transcription factors are regulators of the ApoM/S1P pathway.

Authors

María Concepción Izquierdo, Niroshan Shanmugarajah, Samuel X. Lee, Michael J. Kraakman, Marit Westerterp, Takumi Kitamoto, Michael Harris, Joshua R. Cook, Galina A. Gusarova, Kendra Zhong, Elijah Marbuary, InSug O-Sullivan, Nikolaus Rasmus, Stefania Camastra, Terry G. Unterman, Ele Ferrannini, Barry E. Hurwitz, Rebecca A. Haeusler

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Total citations by year

Year: 2025 2024 2023 2022 Total
Citations: 2 1 4 1 8
Citation information
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Citations to this article (8)

Title and authors Publication Year
Inverse relationship between circulating sphingosine-1-phosphate and precursor species and coronary artery calcification score in type 2 diabetes
Le Goff W, Bourron O, Materne C, Galier S, Phan F, Tan-Chen S, Guillas I, Hartemann A, Salem JE, Redheuil A, Foufelle F, Le Stunff H, Hajduch E, Guerin M
Cardiovascular Diabetology 2025
Unsupervised Learning-Derived Complex Metabolic Signatures Refine Cardiometabolic Risk
Zhou Y, Xiang B, Yang X, Ren Y, Gu X, Zhou X
JACC: Advances 2025
A multi-omics approach identifies the key role of disorders of sphingolipid metabolism in Ang II-induced hypertensive cardiomyopathy myocardial remodeling
Qu Y, Ma D, Wu T, Wang H, Tian Z, Liu X, Wang Y
Scientific Reports 2024
High-Density Lipoprotein Alterations in Type 2 Diabetes and Obesity
Denimal D, Monier S, Bouillet B, Vergès B, Duvillard L
Metabolites 2023
Circulating Sphingolipids and Glucose Homeostasis: An Update
Ali-Berrada S, Guitton J, Tan-Chen S, Gyulkhandanyan A, Hajduch E, Le Stunff H
International journal of molecular sciences 2023
Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice
Izquierdo MC, Harris M, Shanmugarajah N, Zhong K, Ozcan L, Fredman G, Haeusler RA
2023
Macrophage‐derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection
Krejčová G, Morgantini C, Zemanová H, Lauschke VM, Kovářová J, Kubásek J, Nedbalová P, Kamps\u2010Hughes N, Moos M, Aouadi M, Doležal T, Bajgar A
The EMBO Journal 2023
The FOXOs are in the Apo-M House
Macrae Linton
Journal of Clinical Investigation 2022

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