Mechanism of the effect of glycosyltransferase GLT8D2 on fatty liver
Yutao Zhan, Fei Zhao, Ping Xie, Leping Zhong, Dongnian Li, Qujing Gai, Li Li, Hongshan Wei, Lingqiang Zhang, Wei An, Yutao Zhan, Fei Zhao, Ping Xie, Leping Zhong, Dongnian Li, Qujing Gai, Li Li, Hongshan Wei, Lingqiang Zhang, Wei An
Abstract
Background: Recent studies have shown that some glycosyltransferases are involved in the development of nonalcoholic fatty liver disease (NAFLD). The objective of this study was to explore the effect and mechanism of glycosyltransferase GLT8D2 on fatty liver.
Methods: Rat model of NAFLD was established by induction with high-fat-diet. The GLT8D2 expression in rat liver was examined using immunohistochemistry. Oil Red O staining and triglyceride assay were used to measure the effect of abnormal GLT8D2 expression on lipid accumulation in HepG2 cells. The expression levels of lipid metabolism-related key molecules, namely sterol regulatory element-binding protein-1c (SREBP-1c), stearoyl-coA desaturase (SCD), carnitine palmitoyltransferase-1 (CPT1) and microsomal triglyceride transfer protein (MTP), in HepG2 cells with abnormal GLT8D2 expression were determined by western blot analyses.
Results: The expression of GLT8D2 was higher in the liver of rats with NAFLD than in the control rats, and GLT8D2 was mainly located around lipid droplets in hepatocytes. GLT8D2 expression increased in steatosis HepG2 cells compared with that in normal HepG2 cells. GLT8D2 positively regulated lipid droplet accumulation and triglyceride content in HepG2 cells. Upregulation or knockdown of GLT8D2 had no effect on the expressions of SREBP-1c, SCD or CPT-1 proteins in HepG2 cells. However, GLT8D2 expression negatively regulated the expression of MTP protein in HepG2 cells.
Conclusion: GLT8D2 participated in NAFLD pathogenesis possibly by negatively regulating MTP expression. Specific inhibition of GLT8D2 via an antagonistic strategy could provide a potential candidate approach for treatment of NAFLD.
Figures
References
- Moylan CA, Pang H, Dellinger A, Suzuki A, Garrett ME, Guy CD, et al. Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology. 2014;59:471–82. doi: 10.1002/hep.26661.
- Tilg H, Moschen AR. Evolving therapies for non-alcoholic steatohepatitis. Expert Opin Drug Discov. 2014;9:687–96. doi: 10.1517/17460441.2014.911283.
- Fleischman MW, Budoff M, Zeb I, Li D, Foster T, NAFLD prevalence differs among hispanic subgroups The multi-ethnic study of atherosclerosis. World J Gastroenterol. 2014;20:4987–93. doi: 10.3748/wjg.v20.i17.4987.
- Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010;12:83–92. doi: 10.1111/j.1463-1326.2010.01275.x.
- Zhan YT, Weng J, Li L, Xu Q, Song X, Guo XX. Protective effect of probucol on liver injury induced by carbon tetrachloride in rats. Hepatol Int. 2011;5:899–905. doi: 10.1007/s12072-011-9256-0.
- Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51:1820–32. doi: 10.1002/hep.23594.
- Zhan YT, Zhang C, Li L, Bi CS, Song X, Zhang ST. Non-alcoholic fatty liver disease is not related to the incidence of diabetic nephropathy in type 2 diabetes. Int J Mol Sci. 2012;13:14698–706. doi: 10.3390/ijms131114698.
- Zhan YT, An W. Roles of liver innate immune cells in nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:4652–60. doi: 10.3748/wjg.v16.i37.4652.
- Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30:1212–8. doi: 10.2337/dc06-2247.
- Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30:2119–21. doi: 10.2337/dc07-0349.
- Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104:861–7. doi: 10.1038/ajg.2009.67.
- Moon S, Kim SR, Zhao G, Yi J, Yoo Y, Jin P, et al. Rice glycosyltransferase1 encodes a glycosyltransferase essential for pollen wall formation. Plant Physiol. 2013;161:663–75. doi: 10.1104/pp.112.210948.
- Chang A, Singh S, Phillips GN, Jr, Thorson JS. Glycosyltransferase structural biology and its role in the design of catalysts for glycosylation. Curr Opin Biotechnol. 2011;22:800–8. doi: 10.1016/j.copbio.2011.04.013.
- Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, et al. Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest. 2008;118:3725–37. doi: 10.1172/JCI36077.
- Ihara Y, Yoshimura M, Miyoshi E, Nishikawa A, Sultan AS, Toyosawa S, et al. Ectopic expression of N-acetylglucosaminyltransferase III in transgenic hepatocytes disrupts apolipoprotein B secretion and induces aberrant cellular morphology with lipid storage. Proc Natl Acad Sci U S A. 1998;95:2526–30. doi: 10.1073/pnas.95.5.2526.
- Wei HS, Wei HL, Zhao F, Zhong LP, Zhan YT. Glycosyltransferase GLT8D2 positively regulates ApoB100 protein expression in hepatocytes. Int J Mol Sci. 2013;4:21435–46. doi: 10.3390/ijms141121435.
- Nakahara T, Hindsgaul O, Palcic MM, Nishimura S. Computational design and experimental evaluation of glycosyltransferase mutants: engineering of a blood type B galactosyltransferase with enhanced glucosyltransferase activity. Protein Eng Des Sel. 2006;19:571–8. doi: 10.1093/protein/gzl046.
- Benhamed F, Denechaud PD, Lemoine M, Robichon C, Moldes M, Bertrand-Michel J, et al. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J Clin Invest. 2012;122(6):2176–94. doi: 10.1172/JCI41636.
- Zhao F, Xie P, Jiang J, Zhang L, An W, Zhan Y. The effect and mechanism of tamoxifen-induced hepatocyte steatosis in vitro. Int J Mol Sci. 2014;15:4019–30. doi: 10.3390/ijms15034019.
- Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51. doi: 10.1172/JCI23621.
- Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: Old questions and New insights. Science. 2011;332:1519–23. doi: 10.1126/science.1204265.
- Csaki LS, Reue K. Lipins: multifunctional lipid metabolism proteins. Annu Rev Nutr. 2010;30:257–72. doi: 10.1146/annurev.nutr.012809.104729.
- Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A. 2003;100:12027–32. doi: 10.1073/pnas.1534923100.
- Serviddio G, Giudetti AM, Bellanti F, Priore P, Rollo T, Tamborra R, et al. Oxidation of hepatic carnitine palmitoyl transferase-1 (CPT-1) impairs fatty acid beta-oxidation in rats fed a methionine-choline deficient diet. PLoS One. 2011;6:e24084. doi: 10.1371/journal.pone.0024084.
- Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4(1):177–97. doi: 10.1002/cphy.c130024.
- Keung W, Ussher JR, Jaswal JS, Raubenheimer M, Lam VH, Wagg CS, et al. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice. Diabetes. 2013;62:711–20. doi: 10.2337/db12-0259.
- Cryer A. Tissue lipoprotein lipase activity and its action in lipoprotein metabolism. Int J Biochem. 1981;13:525–41. doi: 10.1016/0020-711X(81)90177-4.
- Higashi Y, Itabe H, Fukase H, Mori M, Fujimoto Y, Takano T. Transmembrane lipid transfer is crucial for providing neutral lipids during very low density lipoprotein assembly in endoplasmic reticulum. J Biol Chem. 2003;278:21450–8. doi: 10.1074/jbc.M301376200.
- Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res. 2003;44:22–32. doi: 10.1194/jlr.R200014-JLR200.
Source: PubMed