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

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

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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Figure 2

ApoM expression and HDL-associated S1P are decreased in db/db mice but not diet-induced obese mice.

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ApoM expression and HDL-associated S1P are decreased in db/db mice but n...
(A) Liver Apom gene expression in 13-week-old db/db and db/+ control mice. (B) Liver Apom gene expression in 25-week-old mice. (C) Western blot of ApoM expression in total plasma from 13-week-old and 25-week-old mice. (D) Western blot of ApoM and ApoA1 expression in HDL fractionated by sequential density ultracentrifugation from plasma of 13-week-old and 25-week-old mice. (E) Representative Western blot of ApoM and ApoA1 expression in ultracentrifuge-fractionated lipoproteins from plasma of 13-week-old mice. (F–H) S1P levels in 13-week-old db/db and db/+ control mice. (F) Total plasma S1P levels. (G) Plasma S1P distribution on ultracentrifuge-fractionated lipoproteins. (H) Percentage of plasma S1P distribution. n = 5–6/group. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test.