Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2

Abstract

Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.

Role of Sphingosine Kinase in Type 2 Diabetes Mellitus

“…Overexpression of SphK1 prevents ceramide accumulation in myocytes ameliorates muscle insulin resistance in diet-induced obese mice ( 70 ). SphK has also been found to regulate certain cellular functions via sphingosine, independent of ceramide or S1P: sphingosine specifically impairs SphK1-mediated endocytotic membrane trafficking ( 66 ); sphingosine induces cell cycle arrest in SphK1/SphK2 double knockout murine embryonic stem cells ( 71 ); sphingosine accumulation suppresses insulin signaling in SphK2 deficient hepatocytes ( 7 ); and sphingosine impairs insulin-mediated glucose uptake in L6 myotubes exposed to palmitate ( 72 ).…”

“…In accord, 70-80% of T2D subjects have non-alcoholic fatty liver diseases (NAFLD), and the incidence rate of NAFLD in obese, diabetic individuals is more than 90% ( 5 , 74 ). In the past decade, the role of signaling lipids, including SphK-related sphingolipids like ceramides, sphingosine, and S1P, is emerging in the pathogenesis of hepatic insulin resistance ( 3 , 7 , 75 ).…”

“…The phospho-Akt levels are indistinguishable in the livers of wild-type and Sphk1 -/- mice upon insulin challenge ( 89 ). The insulin response is unchanged in SphK1-knockdown hepatocytes as compared with control cells ( 7 ). Furthermore, S1P impairs hepatic insulin signaling via binding to S1P receptor subtype 2 in HFD-fed New Zealand Obese mice ( 90 ).…”

“…Overexpression of SphK2 in the liver reinforces mitochondrial fatty acid β-oxidation and effectively ameliorates hepatic steatosis, glucose intolerance and insulin resistance in C57BL/6 mice on an HFD ( 95 ). We have recently generated liver-specific Sphk2 -/- (SphK2-LKO) mice by crossbreeding floxed Sphk2 mice with Alb- Cre strain, providing a reliable model to further characterize the role of SphK2 in the liver ( 7 ). SphK2-LKO mice exhibit impaired glucose homeostasis and insulin responsiveness on both normal diet and HFD conditions.…”

“…Sphingolipids are a class of essential intracellular lipids that function as both cell membrane constituents and signaling molecules. Sphingosine kinase (SphK), including the two isoforms SphK1 and SphK2, is a key enzyme of the sphingolipid metabolic pathway ( 7 ). In recent years, an increasing body of evidence has suggested an important role of SphK in T2D, although a certain level of controversy remains.…”