Roles of Sphingolipid Metabolism in Pancreatic β Cell Dysfunction Induced by Lipotoxicity

Abstract

Pancreatic β cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic β cells and pancreatic β cell apoptosis which can favor the development of type 2 diabetes (T2D). Indeed, elevated levels of free fatty acids (FFAs) have been shown to induce β cell apoptosis. Importantly, the chronic adverse effects of FFAs on β cell function and viability are potentiated in the presence of hyperglycaemia, a phenomenon that has been termed gluco-lipotoxicity. The molecular mechanisms underlying the pathogenesis of gluco-lipotoxicity in pancreatic β cells are not completely understood. Recent studies have shown that sphingolipid metabolism plays a key role in gluco-lipotoxicity induced apoptosis and loss of function of pancreatic β cells. The present review focuses on how the two main sphingolipid mediators, ceramides and sphingoid base-1-phosphates, regulate the deleterious effects of gluco-lipotoxicity on pancreatic β cells. The review highlights the role of a sphingolipid biostat on the dysregulation of β cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D.

Keywords: apoptosis; ceramide; gluco-lipotoxicity; insulin; islet of Langherans; obesity; pancreas; sphingolipids; sphingosine-1-phosphate; type 2 diabetes.

Figure 1

Synthesis of sphingolipids in mammalian cells. Two main pathways to produce sphingolipids exist in mammals. The de novo pathway of synthesis starts on the cytoplasmic face of the endoplasmic reticulum (ER). The first step of this pathway is the condensation of l-serine with palmitoyl-CoA to form a 3-ketosphinganine. This reaction is catalyzed by serine palmitoyl-transferase (SPT). 3-Ketosphinganine is then reduced to form dihydrosphingosine (DH-Sph) by 3-ketopshinganine reductase. DH-Sph is a substrate of ceramide synthases (CerS) which produce dihydro-ceramide. Dihydroceramides are transformed into ceramides by dihydroceramide desaturase. Ceramide can be transported to the Golgi apparatus to be transformed into more complex sphingolipids such as sphingomyelin and glucosyl-ceramides. A second synthesis pathway is the catabolic pathway that leads to the degradation of sphingomyelin (SM) into ceramides by sphingomyelinases. This process takes place in the lysosomal and plasma membranes.

Figure 2

Role of sphingolipid biostat in β-cell apoptosis during gluco-lipotoxicity. Palmitate has been shown to induce ceramide accumulation by a dual mechanism involving serine palmitoyl-transferase (SPT) and the formation of ceramides with specific N-acyl chain lengths by ceramide synthase 4 (CerS4). Fatty acid elongase 6 (Elovl-6) provides preferential substrate for CerS4 by converting palmitate into stearate. Ceramides reduces insulin expression through inhibiting the binding of pancreatic and duodenal homeobox 1 (PDX-1) and Mafa transcriptional factors to insulin promoter. Ceramide accumulation can also induce pancreatic β cell apoptosis. However, palmitate also induces sphingosine kinase 1 (SphK1) expression, which will channel the preferential metabolic flow of newly formed dihydrosphingosine (DHSph) towards its phosphorylation into dihydrosphingosine-1-phosphate (DHS1P) and increase S1P levels. Accumulation of these sphingoid base phosphates in the ER will play a protective role against palmitate-induced ceramide-dependent apoptotic β cell death. Sphingoid base phosphates inhibit ceramide synthesis by acting probably on CerS4 activity and restore protein trafficking in the endoplasmic reticulum (ER), alleviating ER stress and attenuating cytochrome C (CytC) release from mitochondria. DH-Cer: dihydro-ceramides; Sph: sphingosine.