한빛사논문
- 조회3,015
Abstract
Su-Yeon Lee1,†, In-Kyung Hong1,†, Bo-Rahm Kim1, Soon-Mi Shim2, Jae Sung Lee3, Hui-Young Lee3, Cheol Soo Choi3, Bo-Kyung Kim4 and Tae-Sik Park1,*
1 Department of Life Science, Gachon University, Sungnam, Gyeonggido, Korea
2 Department of Food Science and Technology, Sejong University, Seoul, Korea
3 Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
4 Department of Physiology, Functional Genomics Institute, School of Medicine, Konkuk University, Seoul, Korea
† Lee, SY and Hong, IK contributed equally to this study.
*Contact information of corresponding author: Tae-Sik Park, Ph.D. Department of Life Science, Gachon University. Sungnam, Gyeonggido, 261-701. South Korea
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 the development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase 2 (Sphk2) is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in liver, was transcriptionally upregulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of the activating transcription factor 4 (ATF4) as demonstrated by promoter assays, immunoblotting and siRNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1-phosphate (S1P) and activated AKT phosphorylation, with no alteration of IRS phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high fat diet led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by high fat diet feeding was reduced by Sphk2-mediated upregulation of fatty acid oxidizing genes and increased fatty acid oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling via Sphk2 upregulation.
Conclusion: Sphk2 is transcriptionally upregulated by acute ER stress via activation of ATF4 and improves perturbed hepatic glucose and fatty acid metabolism. This article is protected by copyright. All rights reserved.
Keywords: sphingosine 1-phosphate; insulin resistance; steatosis; fatty acid oxidation; sphingolipid
논문정보
- Research article
- 2015년 03월 (BRIC 등록일 2015-03-26)
- 국내 연구진
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