Circulating Sphingolipids and Glucose Homeostasis: An Update

Abstract

Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed.

Keywords: biomarkers; ceramides; extracellular vesicles; lipoproteins; sphingosine-1-phosphate.

Figure 1

Regulation of ceramide and sphingosine-1-phosphate levels. Ceramide levels are regulated through three major metabolic pathways: the sphingomyelinase pathway, the de novo pathway, and the salvage pathway. S1P levels are regulated through the de-acylation of ceramide into sphingosine which is then phosphorylated. S1P can be recycled back to sphingosine or irreversibly degraded into hexadecenal and phosphoethanolamine. SPT: serine palmitoyl transferase; KDSR; 3-keto-dihydrosphingosine; CerS: ceramide synthases; DES1: dihydroceramide desaturase-1; GBA: acid β-glucosidase; SMase: sphingomyelinase; CDase: ceramidases; SMase: sphingomyelinase; SMS: sphingomyelin synthase; SphK: sphingosine kinase; SPP: lipid sphingosine phosphatase; SPL: sphingosine-1-phosphate lyase.

Figure 2

Role of sphingolipid transport by lipoproteins in the regulation of type 2 diabetes. Obesity and diabetes are associated with increased levels of ceramide-containing LDL, but also with decreased levels of HDL-S1P. LDL-ceramides were shown to inhibit insulin signaling (decreased phosphorylation of Akt) in muscle. HDL-S1P were shown to promote pancreatic cell function and survival. HDL-S1P can also enhance insulin signaling. Insulin resistance induced by obesity reduces HDL-S1P levels. Both LDL-ceramides and HDL-S1P display opposite actions on the development of T2D. HDL: high density lipoprotein; LDL: low density lipoprotein; S1P: sphingosine-1-phosphate. T2D: type 2 diabetes.

Figure 3

Role of sphingolipid transport by extracellular vesicles in the regulation of type 2 diabetes. Obesity (palmitate) was shown to stimulate the secretion of EVs enriched with ceramide by the liver. EV-ceramide production and secretion are mediated by increased ER stress and a CERT-dependent pathway. Secreted EV-ceramides favor the activation of macrophages, which contributes to NAFLD. Hepatocytes also secrete EV-enriched S1P, which stimulate macrophage chemotaxis, and therefore induce insulin resistance and NAFLD. Both EV-ceramide and EV-S1P secreted by the liver contribute to T2D development. CERT: ceramide transporter; ER: endoplasmic reticulum; EV: extracellular vesicle; NAFLD: non-alcoholic fatty liver disease; S1P; sphingosine-1-phosphate.