Abstract：Objective: To explore the potential pathogenesis of WFS1 gene mutation by bioinformatics analysis of hepatic gene expression profile in Wfs1 knockout mouse. Methods: GSE55143 were downloaded from Gene Expression Omnibus database. Differentially expressed genes were obtained using GEO2R.Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed for differentially expressed genes by online database.Proteinprotein interaction network was established by STRING and visualized by Cytoscape. Results: A total of 198 differentially expressed genes were obtained, including 96 upregulated genes and 102 downregulated genes. GO and KEGG analyses showed that differentially expressed genes were significantly enriched in fatty acid biosynthesis and primary bile acid biosynthesis.Twentysix hub genes were discovered in proteinprotein interaction network. Conclusion: Differentially expressed genes and associated enrichment analyses may help to understand the pathogenesis of WFS1 mutation, thus providing potential targets for treatment.
［1］Inoue H,Tanizawa Y,Wasson J,et al.A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy(Wolfram syndrome)\[J\]. Nat Genet，1998,20(2):143-148.［2］Strom TM,Hrtnagel K,Hofmann S,et al.Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene(wolframin) coding for a predicted transmembrane protein\[J\]. Hum Mol Genet， 1998,7(13):2021-2028.［3］Barrett TG,Bundey SE,Macleod AF.Neurodegeneration and diabetes: UK nationwide study of Wolfram(DIDMOAD) syndrome\[J\].Lancet,1995,346 (8988): 1458-1463.［4］Bansal V,Boehm BO,Darvasi A.Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals\[J\].Diabetologia, 2018,61(10):2180-2188.［5］Punapart M,Eltermaa M,Oflijan J,et al.Effect of chronic valproic acid treatment on hepatic gene expression profile in wfs1 knockout mouse\[J\].PPAR Res,2014:349525.［6］Szklarczyk D, Franceschini A, Wyder S,et al.STRING v10: proteinprotein interaction networks, integrated over the tree of life\[J\].Nucleic Acids Res, 2015,43(Database issue):D447-452.［7］Shannon P,Markiel A,Ozier O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks\[J\].Genome Res, 2003,13(11):2498-2504.［8］Toots M,Reimets R,Plaas M,et al.Muscarinic agonist ameliorates insulin secretion in Wfs1deficient mice\[J\].Can J Diabetes,2019,43(2):115-120.［9］Noormets K, Koks S, Muldmaa M, et al. Sex differences in the development of diabetes in mice with deleted wolframin (Wfs1) gene\[J\]. Exp Clin Endocrinol Diabetes, 2011,119(5):271-275.［10］Porosk R, Terasmaa A, Mahlapuu R, et al. Metabolomics of the Wolfram syndrome 1 gene (Wfs1) deficient mice\[J\]. OMICS, 2017,21(12):721-732.［11］Wakil SJ, AbuElheiga LA. Fatty acid metabolism: target for metabolic syndrome\[J\]. J Lipid Res, 2009,50(Suppl):S138-143.［12］Havula E, Hietakangas V. Sugar sensing by ChREBP/MondoMlxnew insight into downstream regulatory networks and integration of nutrientderived signals\[J\]. Curr Opin Cell Biol, 2018,51:89-96.［13］Guinez C, Filhoulaud G, RayahBenhamed F, et al. OGlcNAcylation increases ChREBP protein content and transcriptional activity in the liver\[J\]. Diabetes, 2011,60(5):1399-1413.［14］Krycer JR, Sharpe LJ, Luu W, et al. The AktSREBP nexus: cell signaling meets lipid metabolism\[J\]. Trends Endocrinol Metab, 2010,21(5):268-276.［15］Kondo M, Tanabe K, AmoShiinoki K, et al. Activation of GLP1 receptor signalling alleviates cellular stresses and improves β cell function in a mouse model of Wolfram syndrome\[J\]. Diabetologia, 2018,61(10):2189-2201.［16］Koks S, Soomets U, PayaCano JL, et al. Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway\[J\]. Physiol Genomics,2009,37(3):249-259.［17］ChavezTalavera O, Tailleux A, Lefebvre P, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease\[J\]. Gastroenterology, 2017,152(7):1679-1694. e3.［18］Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy\[J\]. Pharmacol Rev, 2014,66(4):948-983.［19］Hylemon PB, Zhou H, Pandak WM, et al. Bile acids as regulatory molecules\[J\]. J Lipid Res, 2009,50(8):1509-1520.［20］Sonne DP, van Nierop FS, Kulik W, et al. Postprandial plasma concentrations of individual bile acids and FGF19 in patients with type 2 diabetes\[J\]. J Clin Endocrinol Metab, 2016,101(8):3002-3009.［21］Trauner M, Claudel T, Fickert P, et al. Bile acids as regulators of hepatic lipid and glucose metabolism\[J\]. Dig Dis, 2010,28(1):220-224.［22］Trabelsi MS, Lestavel S, Staels B, et al. Intestinal bile acid receptors are key regulators of glucose homeostasis\[J\]. Proc Nutr Soc, 2017,76(3):192-202.［23］Cheng Z, Liu G, Zhang X, et al. Improvement of glucose metabolism following longterm taurocholic acid gavage in a diabetic rat model\[J\]. Med Sci Monit, 2018,24:7206-7212.
2019, Vol. 29 
