Sphingolipid signaling in metabolic disorders

Abstract

Sphingolipids, ubiquitous membrane lipids in eukaryotes, carry out a myriad of critical cellular functions. The past two decades have seen significant advances in sphingolipid research, and in 2010 a first sphingolipid receptor modulator was employed as a human therapeutic. Furthermore, cellular signaling mechanisms regulated by sphingolipids are being recognized as critical players in metabolic diseases. This review focuses on recent advances in cellular and physiological mechanisms of sphingolipid regulation and how sphingolipid signaling influences metabolic diseases. Progress in this area may contribute to new understanding and therapeutic options in complex diseases such as atherosclerosis, diabetes, metabolic syndromes, and cancer.

Figure 1

Sphingolipid metabolism. Key intermediates are boxed and enzymes are shown in green highlights. Key steps of regulation are indicated with asterisks. *- regulation at the step at the rate-limiting enzyme SPT. Please refer to figure 2 for details. **- ceramide transport from the ER to the Golgi needs the CERT protein which is subject to regulation by cellular signaling pathways. ***- intracellular S1P is secreted by the Spns2 transporter to mediate its extracellular actions on S1P receptors. Intracellular S1P is a key intermediate in the formation of phospholipids (via phosphoethanolamine) and triglycerols (via palmitoyl CoA).

Figure 2

Regulation of SPT enzyme in S. cerevesie. Membrane tension changes or sphingolipid depletion leads to translocation of Slm1 protein and activation of TORC2 complex. This leads to increased activity of the Ypk1 kinase which phosphorylates the ORM complex and thus relieves the inhibitory activity of the SPT enzyme. This results in increased de novo synthesis of sphingolipids.

Figure 3

(A) S1P gradients. Plasma is enriched in S1P due to synthesis by red blood cells, endothelial cells and the liver, which provides ApoM, the physiological S1P carrier on HDL. 65% of plasma S1P is carried by ApoM in HDL whereas the remainder is largely associated with albumin. Lymph contains ~ 20% of plasma S1P which is contributed by lymphatic endothelial cells. In contrast, S1P is tissue interstitial fluids is kept low in part due to the high activity of degradative enzymes such as the S1P lyase. The formation of S1P gradients in critical in its physiological actions in immune and vascular systems. (B) Immune cell egress and S1P gradients. In lymph nodes and other secondary lymphoid organs, low S1P environment allows surface presentation of S1P₁ receptor which is necessary for lymphocyte egress. High S1P in lymph and low S1P in the lymph node is needed for efficient egress. However, the LPP3 lipid phosphatase(Breart et al., 2011) and S1P transporter Spns2(Fukuhara et al., 2012) may allow microgradients of S1P at the nexus of lymphatic endothelium and lymphocytes.

Figure 4

Mechanism of action of sphingolipid mediators. Ceramide is thought to act via alteration of membrane domains and signaling intermediates such as PP2A resulting in the inhibition of the protein kinase Akt. The ability of sphingosine to directly bind to 14-3-3-, ANP32a and the nuclear transcription factor SF1 may also be involved in cellular regulation. S1P is secreted by specific transporters such as Spns2 into the extracellular environment where it accumulates to high levels in plasma. S1P binds to and activates five G protein-coupled receptors (S1P_1–5).