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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1073/pnas.2007856117
Journal or Publication Title: Proceedings of the National Academy of Sciences
Volume: 117
Number: 39
Page Range: pp. 24434-24442
Date: 2020
Divisions: Lipid Cell Biology
Depositing User: General Admin
Identification Number: 10.1073/pnas.2007856117
ISSN: 0027-8424
Date Deposited: 04 Jan 2021 03:03
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.

Creators:
Creators
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Aji, Gulibositan
UNSPECIFIED
Huang, Yu
UNSPECIFIED
Ng, Mei Li
UNSPECIFIED
Wang, Wei
UNSPECIFIED
Lan, Tian
UNSPECIFIED
Li, Min
UNSPECIFIED
Li, Yufei
UNSPECIFIED
Chen, Qi
UNSPECIFIED
Li, Rui
UNSPECIFIED
Yan, Sishan
UNSPECIFIED
Tran, Collin
UNSPECIFIED
Burchfield, James G.
UNSPECIFIED
Couttas, Timothy A.
UNSPECIFIED
Chen, Jinbiao
UNSPECIFIED
Chung, Long Hoa
UNSPECIFIED
Liu, Da
UNSPECIFIED
Wadham, Carol
UNSPECIFIED
Hogg, Philip J.
UNSPECIFIED
Gao, Xin
UNSPECIFIED
Vadas, Mathew A.
UNSPECIFIED
Gamble, Jennifer R.
UNSPECIFIED
Don, Anthony S.
UNSPECIFIED
Xia, Pu
UNSPECIFIED
Qi, Yanfei
UNSPECIFIED
Last Modified: 08 Apr 2021 05:23
URI: https://eprints.centenary.org.au/id/eprint/759

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