Divergent Role of Sphingosine 1-Phosphate on Insulin Resistance

Currently, obesity is a predominant medical condition and an important risk factor for the development of several diseases, including type 2 diabetes mellitus. Importantly, most research has indicated lipid-induced insulin resistance in skeletal muscles is a key link between the aforementioned pathological conditions. PGC-1α is a prominent regulator of myocellular energy metabolism orchestrating gene transcription programming in response to numerous environmental stimuli. Moreover, it is widely acknowledged that mitochondrial metabolism (primary metabolic target of PGC-1α) disturbances are widely acknowledged contributors to type 2 diabetes development. Therefore, it seems surprising that the exact physiological contribution of PGC-1α in the development of insulin resistance in skeletal muscle remains poorly understood. This review aims to reconcile these allegedly different findings by looking for a common denominator in the role(s) of PGC-1α in respect to lipid-induced insulin resistance in skeletal muscle. Our scrutiny of the literature indicates that interventions at the level of PGC-1α may exert beneficial effects on myocytes in respect to lipid-induced insulin resistance. The latter takes place as a result of a positive net energy balance (fatty acids oxidation surpassing their accumulation rate). Moreover, the aforementioned effects may not necessarily be limited to physically active states. They seem to occur, however, only within a physiologically observed range in muscle cells (approximately 1-fold changes in PGC-1α protein expression).

Section: The Lipid-centric View Of Insulin Resistancementioning

confidence: 99%

The Role of PGC-1α in the Development of Insulin Resistance in Skeletal Muscle - Revisited

Łukaszuk

Kurek

Mikłosz

et al. 2015

“…It has been found that LCACoAs and DAGs affect insulin signaling pathway through the activation of serine/threonine PKC isoenzymes [12], whereas Cer inhibits the pathway at Akt/PKB level [13]. Other sphingolipid species such as gangliosides [14] or sphingosine-1-phosphate [15] may also contribute to IR.…”

Section: Introductionmentioning

confidence: 99%

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

Błachnio-Zabielska

Chacińska

Vendelbo

et al. 2016

Background/Aims: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. Methods: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U¹³C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Results: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr-treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl-Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. Conclusion: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats.

“…The precursor ions of S1P (m/z 380.3) and D7-S1P (m/z 387.3) were cleaved into the fragment ions of m/z 264.3 and m/z 271.3 respectively. Ceramides were extracted and quantified as recently described [14]. Briefly, lipid extraction was performed using C17-ceramide as internal standard.…”

Section: Methodsmentioning

confidence: 99%

“…Once generated, ceramides can be further metabolized to the bioactive metabolite sphingosine 1-phosphate (S1P). S1P can be released via specific ATPbinding cassette (ABC)-transporters or via the S1P transporter spinster homolog 2 into the extracellular environment and activates 5 specific G protein-coupled S1P receptors (S1P [1][2][3][4][5] ) in an auto-and paracrine manner [14,15]. In addition to well established effects of S1P in pathogenesis of metabolic diseases, a growing body of evidence indicates that S1P can be considered as an important regulator of fibrosis [16,17].…”

Section: Introductionmentioning

confidence: 99%

Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease

Fadel

Fayyaz

Japtok

et al. 2016

Self Cite

Background/Aims: Ectopic lipid accumulation in hepatocytes has been identified as a risk factor for the progression of liver fibrosis and is strongly associated with obesity. In particular, the saturated fatty acid palmitate is involved in initiation of liver fibrosis via formation of secondary metabolites by hepatocytes that in turn activate hepatic stellate cells (HSCs) in a paracrine manner. Methods: α-smooth muscle actin-expression (α-SMA) as a marker of liver fibrosis was investigated via western blot analysis and immunofluorescence microscopy in HSCs (LX-2). Sphingolipid metabolism and the generation of the bioactive secondary metabolite sphingosine 1-phosphate (S1P) in response to palmitate were analyzed by LC-MS/MS in hepatocytes (HepG2). To identify the molecular mechanism involved in the progression of liver fibrosis real-time PCR analysis and pharmacological modulation of S1P receptors were performed. Results: Palmitate oversupply increased intra- and extracellular S1P-concentrations in hepatocytes. Conditioned medium from HepG2 cells initiated fibrosis by enhancing α-SMA-expression in LX-2 in a S1P-dependent manner. In accordance, fibrotic response in the presence of S1P was also observed in HSCs. Pharmacological inhibition of S1P receptors demonstrated that S1P₃ is the crucial receptor subtype involved in this process. Conclusion: S1P is synthesized in hepatocytes in response to palmitate and released into the extracellular environment leading to an activation of HSCs via the S1P₃ receptor.