Expressed analysis and functional studies of differential expressed lncRNA genes associated with cholesterol gallstone_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

QIAN Changlin , SHEN Zhiyong , ZHANG Jie , QIU Weijing ,  LIU Hua

Department of General Surgery, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201112, P. R. China;

Corresponding?author：

LIU Hua, Email: liuhua1570@renji.com

Keywords：

cholesterol gallstone; long non-coding RNA; gene ontology analysis; kyoto encyclopedia of genes and genomes analysis

DOI：

10.7507/1007-9424.201902072

Video：

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Objective To explore the differential expressed lncRNA genes associated with formation of cholesterol gallstone, and analyze the biological functions of differential expressed lncRNA through bioinformatics.Methods A total of 24 C57BL/6 mice were randomly divided into normal control group (n=8) and lithogenic group (n=16), which were treated with chow diets and lithogenic diets respectively for 5 weeks. After 5 weeks, mice of the lithogenic group were randomly divided into model control group (n=8) and ursodeoxycholic acid treatment group (n=8). Afterwards, mice of the normal control group were still fed with chow diets, mice of the model control group were fed with lithogenic diets, mice of the ursodeoxycholic acid treatment group were fed with ursodeoxycholic acid. After 2 weeks, collected liver tissues and gallbladder bile from the three groups, and observed gallbladder gross sample and analyzed lipids component of gallbladder bile, meanwhile detected the differential expressed lncRNA and analyzed the biological functions of differential expressed lncRNA through bioinformatics, including Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway analysis.Results We successfully constructed the mice model of cholesterol gallstone. Total cholesterol level of gallbladder in the model control group had significantly higher than those of the normal control group and ursodeoxycholic acid treatment group (P<0.05), yet there was no significant difference between the normal control group and ursodeoxycholic acid treatment group (P=0.59). The levels of total bile acid, total bilirubin, and direct bilirubin had no significant difference among the three groups (P>0.05). There were 49 kinds of common overlapped difference lncRNA between the ursodeoxycholic acid treatment group and the model control group through differential expression analysis of lncRNA in liver tissues of the mice in three groups. GO and KEGG path analysis were performed separately by differential expressed lncRNA, and 88 kinds of GO terms and 18 kinds of pathways were significantly enriched from the model control group and the normal control group, 205 kinds of GO terms and 20 kinds of pathways were significantly enriched from the ursodeoxycholic acid treatment group and the normal control group.Conclusions Ursodeoxycholic acid has therapeutic effect for cholesterol gallstone. Differential expressed lncRNAs play an important regulatory role in the formation of cholesterol gallstone and the prevention of gallstone formation by ursodeoxycholic acid treatment, which further lay the foundation in discussing specific mechanism regulated by lncRNA.

Citation： QIAN Changlin, SHEN Zhiyong, ZHANG Jie, QIU Weijing, LIU Hua. Expressed analysis and functional studies of differential expressed lncRNA genes associated with cholesterol gallstone. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(6): 654-661. doi: 10.7507/1007-9424.201902072 Copy

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7.	Vakil N, Everbach EC, Knyrim K. Pathogenesis and treatment of gallstones. N Engl J Med, 1993, 328(25): 1855.
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13.	Asai Y, Yamada T, Tsukita S, et al. Activation of the hypoxia inducible factor 1α subunit pathway in steatotic liver contributes to formation of cholesterol gallstones. Gastroenterology, 2017, 152(6): 1521-1535.
14.	Yang B, Liu B, Bi P, et al. An integrated analysis of differential miRNA and mRNA expressions in human gallstones. Mol Biosyst, 2015, 11(4): 1004-1011.
15.	Adams BD, Parsons C, Walker L, et al. Targeting noncoding RNAs in disease. J Clin Invest, 2017, 127(3): 761-771.
16.	Chen C, Cui Q, Zhang X, et al. Long non-coding RNAs regulation in adipogenesis and lipid metabolism: emerging insights in obesity. Cell Signal, 2018, 51: 47-58.
17.	Zhang L, Yang Z, Trottier J, et al. Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay. Hepatology, 2017, 65(2): 604-615.
18.	Zeng Y, Ren K, Zhu X, et al. Long noncoding RNAs: advances in lipid metabolism. Adv Clin Chem, 2018, 87: 1-36.
19.	Li Y, Shen S, Ding S, et al. LincRNA DYN-LRB2-2 upregulates cholesterol efflux by decreasing TLR2 expression in macrophages. J Cell Biochem, 2018, 119(2): 1911-1921.
20.	Sallam T, Jones MC, Gilliland T, et al. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature, 2016, 534(7605): 124-128.
21.	Lan X, Yan J, Ren J, et al. A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology, 2016, 64(1): 58-72.
22.	Hennessy EJ, van Solingen C, Scacalossi KR, et al. The long noncoding RNA CHROME regulates cholesterol homeostasis in primates. Nature Metabolism, 2018, 1(1): 98-110.
23.	劉清, 金俊哲, 呂洪洋, 等. 膽囊結石的相關危險因素分析. 中國普外基礎與臨床雜志, 2016, 23(12): 1492-1495.
24.	馬文杰, 陳巍巍, 楊琴, 等. 以核磁共振方法測定膽囊結石患者的氨基酸譜及糖代謝譜的初步臨床研究. 中國普外基礎與臨床雜志, 2018, 25(4): 401-409.
25.	Pasternak A, Bugajska J, Szura M, et al. Biliary polyunsaturated fatty acids and telocytes in gallstone disease. Cell Transplant, 2017, 26(1): 125-133.
26.	Shabanzadeh DM, Skaaby T, S?rensen LT, et al. Metabolic biomarkers and gallstone disease - a population-based study. Scand J Gastroenterol, 2017, 52(11): 1270-1277.

1. Gurusamy KS, Davidson BR. Gallstones. BMJ, 2014, 348: g2669.
2. 王啟晗, 張中文, 吳健, 等. 上海地區膽囊結石病的流行病學調查. 外科理論與實踐, 2018, 23(3): 252-257.
3. Di Ciaula A, Wang DQ, Portincasa P. An update on the pathogenesis of cholesterol gallstone disease. Curr Opin Gastroenterol, 2018, 34(2): 71-80.
4. Di Ciaula A, Wang DQ, Bonfrate L, et al. Current views on genetics and epigenetics of cholesterol gallstone disease. Cholesterol, 2013, 2013: 298421.
5. Lammert F, Gurusamy K, Ko CW, et al. Gallstones. Nat Rev Dis Primers, 2016, 2: 16024.
6. 譚志輝, 張先林. 膽固醇結石形成的相關性因素研究. 中國普外基礎與臨床雜志, 2016, 23(1): 123-126.
7. Vakil N, Everbach EC, Knyrim K. Pathogenesis and treatment of gallstones. N Engl J Med, 1993, 328(25): 1855.
8. 陳敏, 張濤, 克力木. ApoB基因rs676210和rs2854725位點多態性與膽囊結石的相關性研究. 中國普外基礎與臨床雜志, 2017, 24(2): 215-221.
9. Chen Q, Li WJ, Wan YY, et al. Fibroblast growth factor receptor 4 Gly388Arg polymorphism associated with severity of gallstone disease in a Chinese population. Genet Mol Res, 2012, 11(1): 548-555.
10. Song KH, Li T, Owsley E, et al. A putative role of micro RNA in regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes. J Lipid Res, 2010, 51(8): 2223-2233.
11. Pascual G, Avgustinova A, Mejetta S, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature, 2017, 541(7635): 41-45.
12. Xie Y, Cifarelli V, Pietka T, et al. Cd36knockout mice are protected against lithogenic diet-induced gallstones. J Lipid Res, 2017, 58(8): 1692-1701.
13. Asai Y, Yamada T, Tsukita S, et al. Activation of the hypoxia inducible factor 1α subunit pathway in steatotic liver contributes to formation of cholesterol gallstones. Gastroenterology, 2017, 152(6): 1521-1535.
14. Yang B, Liu B, Bi P, et al. An integrated analysis of differential miRNA and mRNA expressions in human gallstones. Mol Biosyst, 2015, 11(4): 1004-1011.
15. Adams BD, Parsons C, Walker L, et al. Targeting noncoding RNAs in disease. J Clin Invest, 2017, 127(3): 761-771.
16. Chen C, Cui Q, Zhang X, et al. Long non-coding RNAs regulation in adipogenesis and lipid metabolism: emerging insights in obesity. Cell Signal, 2018, 51: 47-58.
17. Zhang L, Yang Z, Trottier J, et al. Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay. Hepatology, 2017, 65(2): 604-615.
18. Zeng Y, Ren K, Zhu X, et al. Long noncoding RNAs: advances in lipid metabolism. Adv Clin Chem, 2018, 87: 1-36.
19. Li Y, Shen S, Ding S, et al. LincRNA DYN-LRB2-2 upregulates cholesterol efflux by decreasing TLR2 expression in macrophages. J Cell Biochem, 2018, 119(2): 1911-1921.
20. Sallam T, Jones MC, Gilliland T, et al. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature, 2016, 534(7605): 124-128.
21. Lan X, Yan J, Ren J, et al. A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology, 2016, 64(1): 58-72.
22. Hennessy EJ, van Solingen C, Scacalossi KR, et al. The long noncoding RNA CHROME regulates cholesterol homeostasis in primates. Nature Metabolism, 2018, 1(1): 98-110.
23. 劉清, 金俊哲, 呂洪洋, 等. 膽囊結石的相關危險因素分析. 中國普外基礎與臨床雜志, 2016, 23(12): 1492-1495.
24. 馬文杰, 陳巍巍, 楊琴, 等. 以核磁共振方法測定膽囊結石患者的氨基酸譜及糖代謝譜的初步臨床研究. 中國普外基礎與臨床雜志, 2018, 25(4): 401-409.
25. Pasternak A, Bugajska J, Szura M, et al. Biliary polyunsaturated fatty acids and telocytes in gallstone disease. Cell Transplant, 2017, 26(1): 125-133.
26. Shabanzadeh DM, Skaaby T, S?rensen LT, et al. Metabolic biomarkers and gallstone disease - a population-based study. Scand J Gastroenterol, 2017, 52(11): 1270-1277.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expressed analysis and functional studies of differential expressed lncRNA genes associated with cholesterol gallstone

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