Abstract
Ceramide is a key compound in sphingolipid metabolism. Dynamics of ceramide synthesis is important in the several biological processes, such as induction of apoptosis or insulin resistance. So far, its de novo synthesis rate was evaluated indirectly, based on the content of the compound, its intermediates and the activity of respective enzymes. The aim of the present study was to directly measure ceramide synthesis rate (FSR) in different muscle types under varied plasma FFA supply in rat with the use of [U-13C] palmitate tracer and LC/MS/MS. The experiments were carried out on male Wistar rats, divided into three groups: 1-control, 2-with elevated plasma free fatty acid (FFA) concentration by means of intralipid and heparin, 3-with reduced plasma FFA concentration by means of nicotinic acid. The stable plasma FFA concentration and plasma [U-13C] palmitate enrichment was maintained for two hours by simultaneous infusion of the tracer and the respective compounds. At the end of the experiment, samples of blood from the abdominal aorta, the heart, diaphragm, soleus and white section of the gastrocnemius were taken. Muscle sphinganine, sphingosine and ceramide content and enrichment and plasma palmitate enrichment was measured with the use of LC/MS/MS. Plasma FFA concentration and composition was measured by means of gas-liquid chromatography. Under basal conditions ceramide FSR in the heart and the diaphragm was higher than in the soleus and the white gastrocnemius. Elevation in the plasma FFA concentration increased the FSR and ceramide content in each muscle, which correlated with increased HOMA-IR. The highest FSR was noted in the heart. Reduction in the plasma FFA concentration decreased ceramide FSR in each muscle type, which was accompanied by marked reduction in HOMA-IR. It is concluded that ceramide FSR depends on both the muscle type and the plasma FFA supply and is correlated with whole body insulin sensitivity under varying plasma FFA supply.
Highlights
Ceramide is the key compound in metabolism of sphingolipids
The results obtained on plasma FFA metabolism clearly show that the procedures of elevation and reduction in the plasma free fatty acid concentration worked as expected
The changes in plasma fatty acids concentration were accompanied by respective change in whole body insulin sensitivity, as estimated by homeostasis model assessment of insulin resistance (HOMA-IR)
Summary
Ceramide is the key compound in metabolism of sphingolipids It consists the core of all complex sphingolipids and acts as a precursor of sphingosine and ceramide-1-phosphate [1, 2]. There are four sources of ceramide (Fig 1): 1- de novo synthesis, 2- liberation from complex sphingolipids, 3- acylation of sphingosine and 4—dephosphorylation of ceramide-1-phosphate [1, 2]. De novo pathway of ceramide synthesis is the most important one, since it is the source of all derivatives of ceramide including the complex sphingolipids. The 2–4 sources are secondary ones, since ceramide had to be first incorporated in these compounds Those sources can be regarded as salvage pathways of ceramide generation, where ceramide or sphingosine backbone comes from complex sphingolipids. Detailed description of ceramide synthesis and salvage pathways are presented in the Fig 1
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