The FoxOs are in the ApoM house
MacRae F. Linton, … , Zoe M. Leuthner, Jonathan D. Brown
MacRae F. Linton, … , Zoe M. Leuthner, Jonathan D. Brown
Published April 1, 2022
Citation Information: J Clin Invest. 2022;132(7):e158471. https://doi.org/10.1172/JCI158471.
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The FoxOs are in the ApoM house

Abstract

The prevalence of metabolic syndrome continues to increase globally and heightens the risk for cardiovascular disease (CVD). Insulin resistance is a core pathophysiologic mechanism that causes abnormal carbohydrate metabolism and atherogenic changes in circulating lipoprotein quantity and function. In particular, dysfunctional HDL is postulated to contribute to CVD risk in part via loss of HDL-associated sphingosine-1-phosphate (S1P). In this issue of the JCI, Izquierdo et al. demonstrate that HDL from humans with insulin resistance contained lower levels of S1P. Apolipoprotein M (ApoM), a protein constituent of HDL that binds S1P and controls bioavailability was decreased in insulin-resistant db/db mice. Gain- and loss-of-function mouse models implicated the forkhead box O transcription factors (FoxO1,3,4) in the regulation of both ApoM and HDL-associated S1P. These data have important implications for potential FoxO-based therapies designed to treat lipid and carbohydrate abnormalities associated with human metabolic disease and CVD.

Authors

MacRae F. Linton, Patricia G. Yancey, Zoe M. Leuthner, Jonathan D. Brown

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Figure 1

FoxO1,3,4 regulate plasma levels of the HDL-ApoM-S1P complex.

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FoxO1,3,4 regulate plasma levels of the HDL-ApoM-S1P complex. Hepatic Fo...
Hepatic FoxO transcription factors control the expression of Apom by binding to the promoter and enhancer regions of the gene. ApoM is secreted and forms a complex with plasma S1P. The majority of plasma ApoM-S1P associates with HDL and is found to be associated with pre-β and α (HDL2 and HDL3) migrating subpopulations. ApoM may stimulate the formation of pre–β-HDL during the endothelial lipase– (EL-) and hepatic lipase–mediated (HL-mediated) conversion of α-HDL2 to HDL3 and pre–β-HDL. The HDL-ApoM-S1P complex enhances endothelial barrier integrity and vasodilation. The roles for the HDL-ApoM-S1P complex in insulin resistance, HDL CEC, and RCT have not been clearly demonstrated. FC, free cholesterol; LCAT, lecithin-cholesterol acyltransferase; PL, phospholipid.