Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice

Abstract

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.

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

“…This illustrates that bile acid activation of S1PR2 has insulin-like activity in hepatic glucose regulation (9). Further, it has been reported that hepatic overexpression of SphK2 in mice led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver, and ameliorated glucose intolerance and insulin resistance by improving hepatic insulin signaling (44). Considering that SphK2 can be activated by conjugated bile acids via S1PR2, which results in elevation of S1P and reduction of ceramide, sphingomyelin, and glucosylceramide, both S1PR2 and SphK2 appear to play important roles in hepatic glucose metabolism (Fig.…”

“…In fact, mice deficient in SphK2 also rapidly developed fatty livers on a high-fat diet, suggesting the importance of S1PR2 and SphK2 in regulating liver lipid metabolism (9,11). In mice fed a high-fat diet, overexpression of SphK2 led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and in the liver (44). In response to accumulation of lipids in the liver, SphK2 facilitates upregulation of genes encoding enzymes in fatty acid transport and oxidation (44).…”

“…In mice fed a high-fat diet, overexpression of SphK2 led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and in the liver (44). In response to accumulation of lipids in the liver, SphK2 facilitates upregulation of genes encoding enzymes in fatty acid transport and oxidation (44).…”

The role of sphingolipid signalling in diabetes-associated pathologies (Review)

“…The overexpression of the SphK2 gene has been shown to elevate hepatic S1P expression and improve glucose/lipid metabolism in KK/Ay diabetic mice. The adenoviral-mediated expression of SphK2 activated the Akt pathway, a key signalling mechanism in the insulin-induced regulation of glucose metabolism, thus, confirming an important role of SphK2 in regulating hepatic insulin signalling (47). …”

“…Hepatic insulin resistance has been confirmed as the major risk factor for T2D onset. Previous studies have shown that SphK activation improves hepatic insulin signalling in obesity and diabetes (43–45,47). Notably, in a previous study, low total SphK activity was detected in the livers of mice fed a high-fat diet (HFD).…”