Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Abstract

Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…These lipid mediators have been associated with the activation of the inflammatory response, ROS production, mitochondrial dysfunction, autophagy deregulation, endoplasmic reticulum stress (ER stress) and apoptosis [69,80,81]. This fact is mainly due to the accumulation of intermediary toxic metabolites, such as diacylglycerol, fatty acyl-CoA, ceramides, and sphingolipids, which are involved in protein kinase C (PKC) activation, triglyceride synthesis, and mitochondrial dysfunction [82,83].…”

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

“…Ceramides are synthesized in all metabolic tissues in HFD-fed rodents and obese humans, and have been linked to IR as reviewed in detail in previous issues of the journal [ 16 , 47 ]. This appears to be independent of an increased dietary intake of ceramides, resulting rather from an increased cellular endogenous production either due to increased substrate availability or changes in synthesis enzymes [ 47 , 48 , 49 ].…”

“…This appears to be independent of an increased dietary intake of ceramides, resulting rather from an increased cellular endogenous production either due to increased substrate availability or changes in synthesis enzymes [ 47 , 48 , 49 ]. Synthesis and degradation pathways and their regulation, which govern total ceramide content, have been extensively reviewed in the past few years [ 16 , 48 , 49 ]. Ceramides are mainly produced through de novo synthesis ( Figure 1 ).…”

“…An inverse association between intramyocellular TAG (IMTG) content and peripheral glucose disposal has been repeatedly reported in sedentary subjects [ 13 , 14 , 15 ]. It is now well established that IMTG is associated with elevated levels of lipotoxic intermediates such as DAGs and ceramides that inhibit insulin signaling and interfere with glucose metabolism as previously discussed elsewhere [ 16 , 17 , 18 ]. However, a growing body of data indicates that subcellular localization and composition of these bioactive lipids is a better predictor of IR than their total pool [ 19 , 20 ].…”

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

“…The increased bioactive lipid in obesity, ceramide, contributes to insulin resistance and lipotoxicity. The quantification of plasma ceramide as a biomarker could predict major adverse cardiac events [80][81][82][83]. Zhu and colleagues showed that ASAH2 treatment might overcome palmitic acid (PA)-induced insulin resistance and also block PA-induced oxidative stress where ceramide is involved (Table 3) [84,85].…”