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Review
. 2012 May-Jun;4(3):177-87.
doi: 10.4161/isl.20102.

Roles of ceramide and sphingolipids in pancreatic β-cell function and dysfunction

Ebru Boslem  1 , Peter J Meikle, Trevor J Biden
Affiliations
Review

Roles of ceramide and sphingolipids in pancreatic β-cell function and dysfunction

Ebru Boslem et al. Islets. 2012 May-Jun.

Abstract

Recent technical advances have re-invigorated the study of sphingolipid metabolism in general, and helped to highlight the varied and important roles that sphingolipids play in pancreatic β-cells. Sphingolipid metabolites such as ceramide, glycosphingolipids, sphingosine 1-phosphate and gangliosides modulate many β-cell signaling pathways and processes implicated in β-cell diabetic disease such as apoptosis, β-cell cytokine secretion, ER-to-golgi vesicular trafficking, islet autoimmunity and insulin gene expression. They are particularly relevant to lipotoxicity. Moreover, the de novo synthesis of sphingolipids occurs on many subcellular membranes, in parallel to secretory vesicle formation, traffic and granule maturation events. Indeed, the composition of the plasma membrane, determined by the activity of neutral sphingomyelinases, affects β-cell excitability and potentially insulin exocytosis while another glycosphingolipid, sulfatide, determines the stability of insulin crystals in granules. Most importantly, sphingolipid metabolism on internal membranes is also strongly implicated in regulating β-cell apoptosis.

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Figures

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Figure 1. Ceramide synthesis. The first step of de novo ceramide synthesis involves the condensation of palmitoyl-CoA and serine by serine palmitoyltransferase. Other long-chain fatty acyl-CoAs, commonly 14 to 26 carbons long can also be incorporated as a side-chain following sphinganine synthesis by 3-ketosphinganine reductase (not shown, see Figure 2) by the action of ceramide synthases 1–6. These synthases, also known as longevity assurance homologs (Lass) 1–6, have different chain length specificities in regard to their fatty acyl-CoA substrates. Following ceramide breakdown to its sphingosine backbone by neutral or acidic ceramidases (CDase) within different subcellular compartments, the sphingosine is transported out of the lysosome and can be reincorporated back into ceramide via ceramide synthase. This salvage pathway of ceramide synthesis utilizes the same ceramide synthases involved in the de novo pathway.
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Figure 2. Sphingolipid synthesis and its subcellular topology. The synthesis of the central sphingolipid, ceramide, begins with the de novo pathway at the surface of the endoplasmic reticulum (ER) and the condensation of palmitoyl-CoA and serine by serine palmitoyl transferase 1 (SPT). Ceramide is transported to the golgi by ceramide transport protein (CERT) where glucosylceramide (GluCer) and sphingomyelin (SM) are synthesized. Ceramide is a precursor for subspecies ceramide-1-phosphate (C-1-P) and galactosylceramide (GalCer) within neutral compartments. GalCer may be sulphated forming sulfatide which associates with insulin crystals within granules. Higher glycosphingolipids (GSLs) such as gangliosides are formed at the trans-golgi then delivered to the plasma membrane (PM) along with ceramide and SM. SM can produce localized increases in ceramide via activation of the sphingomyelinase (SMase) pathway which causes association of ceramide with cholesterol and GSLs in subpools of the PM termed detergent resistant membranes. GSLs, SM and ceramide are degraded to sphingosine (Sph) in the late endosomes and lysosomes. Sphingosine exits the lysosome and may either be salvaged back into ceramide or form sphingosine-1-phosphate (S-1-P), a key lipid signaling intermediate, which can be terminally degraded to ethanolamine phosphate and hexadecenal. Dotted lines indicate salvage/recycling pathways, whereas solid lines signify de novo synthesis. SMase, sphingomyelinase; SMS1/2, sphingomyelin synthase 1/2; GCS, glucosylceramide synthase; CerS, ceramide synthase; GalTase, galactosyltransferase; SK, sphingosine kinase; CK, ceramide kinase; CDase, ceramidase; S1P lyase, sphingosine-1-phosphate lyase; SPPase, sphingosine-1-phosphate phosphatase.
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