Sphingosine Kinase 1 Is Regulated by Peroxisome Proliferator-activated Receptor α in Response to Free Fatty Acids and Is Essential for Skeletal Muscle Interleukin-6 Production and Signaling in Diet-induced Obesity

Abstract

Background:The fatty acid palmitate induces sphingosine kinase 1 (Sphk1) activity in skeletal muscle by an unknown mechanism. Results: SphK1 is transcriptionally up-regulated by peroxisome proliferator-activated receptor ␣ in lipid overload and promotes interleukin (IL)-6 expression and signaling. Conclusion: Palmitate-induced IL-6 is SphK1-dependent and mediates paracrine/autocrine IL-6 signaling in muscle. Significance: This study identifies a novel role for SphK1 in the context of obesity.

SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes

“…Assays were carried out but we have also shown roles for saturated fatty acids in increasing enzymes of sphingolipid metabolism. For example, we previously observed that lipid oversupply (as occurs in metabolic disease, the physiological context of NAFLD) induced sphingosine kinase 1 (SphK1) ( 7,13 ), a fi nding that has since been corroborated by other groups (14)(15)(16). These studies were the fi rst to demonstrate fatty acid-mediated induction of SphK1 transcription, and perhaps more importantly, placed SphK1 in the context of cell lipotoxicity and metabolic disease.…”

“…A recent study from our laboratory demonstrated that dietary fat composition (i.e., saturated vs. unsaturated) had a profound effect on deleterious liver outcomes, including ER stress, liver weight, and hepatic steatosis, which are components of NAFLD ( 22,(26)(27)(28)(29)(30). Moreover, other studies in our laboratory and others indicated that palmitate (C16:0), but not oleate (C18:1), increased expression of SphK1 in skeletal muscle, and that the enzyme was required for expression of proinfl ammatory genes in primary skeletal muscle cells and also in skeletal muscle in mice on a highfat diet ( 7,13 ). Additionally, we demonstrated that highfat diet-mediated induction of proinfl ammatory cytokines in skeletal muscle was impaired in SphK1 Ϫ / Ϫ mice ( 13 ).…”

“…Similar to hepatocytes, palmitate induced sphingosine kinase ( Fig. 5A ) glucose-induced infl ammation in endothelial cells and IL-6 production and signaling in skeletal muscle and adipose tissue, respectively ( 13,33 ). Therefore, whether the net contribution of SphK1 is ultimately protective or deleterious in the obese/diabetic context remains unresolved, and identifi cation of individual receptors that mediate distinct effects may facilitate targeting this pathway for specifi c clinical interventions.…”

Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

“…It was shown that high fat diet treatment caused a SphK1-dependent up-regulation of IL-6 in muscle, whereas high fat diet had no effect on the IL-6 levels in adipose tissue (46). In contrast, Wang et al (37) recently observed that high fat diet triggered adipose inflammation (including up-regulation of IL-6), which was dependent on SphK1 activity.…”

“…Palmitate treatment enhanced SphK1 expression in C2C12 myotubes (45). The study of Ross et al (46) suggested that peroxisome proliferator-activated receptor ␣ is involved in the palmitate-induced SphK1 expression in muscle. In contrast, we found that the stress kinase JNK/AP-1 signaling cascade 3T3-L1 cells were transfected with sequence specific si-SphK1, si-SphK2, or non-targeting control (NC) siRNA oligonucleotides (50 nM, Invitrogen).…”