Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.
Gulibositan AjiYu HuangMei Li NgWei WangTian LanMin LiYufei LiQi ChenRui LiSishan YanCollin TranJames G BurchfieldTimothy A CouttasJinbiao ChenLong Hoa ChungDa LiuCarol WadhamPhilip J HoggXin GaoMathew A VadasJennifer R GambleAnthony Simon DonPu XiaJacob Yanfei QiPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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.
Keyphrases
- type diabetes
- signaling pathway
- pi k akt
- insulin resistance
- blood glucose
- glycemic control
- liver injury
- drug induced
- adipose tissue
- transcription factor
- tyrosine kinase
- cell proliferation
- skeletal muscle
- high fat diet
- polycystic ovary syndrome
- machine learning
- blood pressure
- artificial intelligence
- high glucose
- fluorescent probe
- living cells
- weight loss
- diabetic rats