Reducing Plasma Membrane Sphingomyelin Increases Insulin Sensitivity
- 1 October 2011
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 31 (20), 4205-4218
- https://doi.org/10.1128/mcb.05893-11
Abstract
It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits. Homozygous Sptlc2-deficient mice are embryonic lethal. However, heterozygous Sptlc2-deficient mice that were viable and without major developmental defects demonstrated decreased ceramide and sphingomyelin levels in the cell plasma membranes, as well as heightened sensitivity to insulin. Moreover, these mutant mice were protected from high-fat diet-induced obesity and insulin resistance. SMS is the last enzyme for sphingomyelin biosynthesis, and SMS2 is one of its isoforms. Sms2 deficiency increased cell membrane ceramide but decreased SM levels. Sms2 deficiency also increased insulin sensitivity and ameliorated high-fat diet-induced obesity. We have concluded that Sptlc2 heterozygous deficiency- or Sms2 deficiency-mediated reduction of SM in the plasma membranes leads to an improvement in tissue and whole-body insulin sensitivity.Keywords
This publication has 75 references indexed in Scilit:
- Dynamic Modification of Sphingomyelin in Lipid Microdomains Controls Development of Obesity, Fatty Liver, and Type 2 DiabetesOnline Journal of Public Health Informatics, 2011
- Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ERThe Journal of cell biology, 2009
- Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificitiesProceedings of the National Academy of Sciences of the United States of America, 2009
- Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organizationBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2007
- Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistanceProceedings of the National Academy of Sciences of the United States of America, 2007
- Resistance to alkyl-lysophospholipid-induced apoptosis due to downregulated sphingomyelin synthase 1 expression with consequent sphingomyelin- and cholesterol-deficiency in lipid raftsBiochemical Journal, 2006
- Insulin signalling and the regulation of glucose and lipid metabolismNature, 2001
- Loss of Caveolae, Vascular Dysfunction, and Pulmonary Defects in Caveolin-1 Gene-Disrupted MiceScience, 2001
- Cholesterol Depletion Disrupts Caveolae and Insulin Receptor Signaling for Metabolic Control via Insulin Receptor Substrate-1, but Not for Mitogen-activated Protein Kinase ControlOnline Journal of Public Health Informatics, 2001
- Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein EScience, 1992