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Review
. 2008 Jun;29(4):381-402.
doi: 10.1210/er.2007-0025. Epub 2008 May 1.

Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights From in Vivo Manipulation of Sphingolipid Metabolism

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Free PMC article
Review

Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights From in Vivo Manipulation of Sphingolipid Metabolism

William L Holland et al. Endocr Rev. .
Free PMC article

Abstract

Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid milieu in most tissues, may be among the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g., saturated fatty acids, inflammatory cytokines) selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic beta-cell failure, cardiomyopathy, and vascular dysfunction. However, definitive evidence that sphingolipids contribute to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, beta-cell failure, cardiomyopathy, and vascular dysfunction, focusing on these in vivo studies that identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease.

Figures

Figure 1
Figure 1
Schematic diagram illustrating sphingolipid synthesis and metabolism. 1) Serine palmitoyltransferase catalyzes the condensation of serine and palmitoyl CoA. 2) 3-Ketosphinganine reductase catalyzes sphinganine formation. 3) Dihydroceramide synthases add a second acyl chain to sphinganine resulting in dihydroceramide formation. 4) Dihydroceramide desaturase catalyzes formation of bioactive ceramide. 5) Ceramidase deacylates ceramide to form sphingosine and fatty acid. 6) Ceramide kinase phosphorylates ceramide to form ceramide 1-phosphate. 7) Glucosylceramide synthase adds glucose, an initial step in ganglioside formation. 8) Sphingomyelin synthase promotes the addition of phosphocholine to ceramide. 9) Sphingomyelinase regenerates ceramide and choline from the breakdown of sphingomyelin.
Figure 2
Figure 2
Schematic diagram illustrating the canonical insulin signaling pathway. The insulin receptor (IR) phosphorylates itself as well as IRS. PI3 kinase (PI3K) phosphorylates 3-phosphoinositides, which produce binding sites for PIP3 dependent kinase (PDK) and Akt via their PH domains. Akt is phosphorylated by PDK and mTOR-Rictor, which lead to active Akt kinase activity and its pleiotropic effects. P denotes key phosphorylation events.
Figure 3
Figure 3
Schematic diagram depicting the multiple mechanisms by which sphingolipids impair insulin action. Top, GM3 gangliosides present in detergent-resistant microdomains (DRD) displace the insulin receptor from these domains and prevent insulin receptor activation. Ceramide (CER) may lead to activation of IKK and c-Jun N-terminal kinase, which inhibit IRS via serine phosphorylation (S-P). Bottom, Ceramide activates PKCζ, which via phosphorylation on Akt’s PH domain prevents binding to 3-phosphoinositides that aid in Akt activation. Additionally, ceramide activates PP2A, which impairs Akt activity via removal of activating phosphate residues.
Figure 4
Figure 4
This schematic depicts the production of S1P by sphingosine kinase and its resulting roles as both an extracellullar ligand for S1P receptors and a putative intracellular messenger. Akt/PKB and MAPK are serine/threonine kinases shown previously to stimulate β-cell survival or proliferation, respectively.

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