The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up-regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high-fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2-mediated up-regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up-regulation. Conclusion: Sphk2 is transcriptionally up-regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism. (HEPATOLOGY 2015;62:135-146) O besity developed by consumption of excess nutrients is a major contributor to the development of metabolic dysfunctions, such as insulin resistance, hypertension, and cardiovascular events.

Obesity is a metabolic disorder developed by overnutrition and a major cause for insulin resistance and cardiovascular events. Since adipose tissue is one of the major sites for the synthesis and secretion of cytokines, enlarged adipose tissue in obese condition alters inflammatory state leading to pathophysiological conditions such as type 2 diabetes and increased cardiovascular risk. A plausible theory for development of metabolic dysregulation is that obesity increases secretion of inflammatory cytokines from adipose tissue and causes a chronic inflammation in the whole body. Additionally accumulation of lipids in non-adipose tissues elevates the cellular levels of bioactive lipids that inhibit the signaling pathways implicated in metabolic regulation together with activated inflammatory response. Recent findings suggest that obesity-induced inflammatory response leads to modulation of sphingolipid metabolism and these bioactive lipids may function as mediators for increased risk of metabolic dysfunction. Importantly, elucidation of mechanism regarding sphingolipid metabolism and inflammatory disease will provide crucial information to development of new therapeutic strategies for the treatment of obesity-induced pathological inflammation.