Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2
Open Access
- 29 September 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (39), 24434-24442
- https://doi.org/10.1073/pnas.2007856117
Abstract
Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.Funding Information
- Department of Health | National Health and Medical Research Council (APP1162545)
- Department of Health | National Health and Medical Research Council (APP1113527)
- National Natural Science Foundation of China (81561128014)
- National Natural Science Foundation of China (81870559)
- University of Sydney | Sydney Medical School (1045555)
This publication has 48 references indexed in Scilit:
- Biological Characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a Selective Sphingosine Kinase-2 Inhibitor and Anticancer AgentPLOS ONE, 2013
- Characterization of Isoenzyme-Selective Inhibitors of Human Sphingosine KinasesPLOS ONE, 2012
- Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1Biochemical Journal, 2012
- Sphingosine‐1‐phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respirationThe FASEB Journal, 2010
- Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their functionCellular Signalling, 2010
- Inhibition of De Novo Ceramide Synthesis Reverses Diet-Induced Insulin Resistance and Enhances Whole-Body Oxygen ConsumptionDiabetes, 2010
- Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-PhosphateScience, 2009
- Ceramide Synthase Inhibition by Fumonisin B1 Treatment Activates Sphingolipid-Metabolizing Systems in Mouse LiverToxicological Sciences, 2006
- Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720Online Journal of Public Health Informatics, 2004
- Identification of 14-3-3ζ as a Protein Kinase B/Akt SubstrateOnline Journal of Public Health Informatics, 2002