Role of PI3K/Akt/mTOR Signaling Pathway in Liver Injury Induced by Severe Acute Pancreatitis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 OUYANGJun ¹ , ZHOUYue-xian ² ,  LIXi ¹ , ZHANGZhao-hui ¹ , NIUWan-cheng ¹

1. Department of General Surgery, Affiliated Huaihai Hospital of Xuzhou Medical College, Xuzhou 221000, Jiangsu Province, China;
2. Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, China;

Corresponding author：

LIXi, Email: lixi97@163.com

Keywords：

Severe acute pancreatitis; PI3K/Akt/mTOR signaling pathway; Liver injury

DOI：

10.7507/1007-9424.20150148

Video：

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Objective To investigate the effect of PI3K/Akt/mTOR signaling pathway on liver injury induced by severe acute pancreatitis (SAP). Methods Forty healthy adult male Sprague-Dawley (SD) rats were randomly divided into 4 groups: Sham operation group (SO group), SAP group, PI3K inhibitor LY294002 group (LY294002 group), and mTOR kinase inhibitor rapamycin group (rapamycin group). The rat model with SAP was made by injection with 5% sodium deoxycholate through retrogradely bilio pancreatic duct. Serum levels of amylase (AMY), alanine aminotransferase (ALT), and aspartate transaminase (AST) were detected through the inferior vena at 6 h after modeling. Pathologic change of the liver was observed under the light microscope. TUNEL analysis was used to detect apoptotic index (AI) of the heptocyte. Expressions of Akt, phosphated-Akt (p-Akt), mTOR, phosphated-mTOR (p-mTOR) protein were evaluated by Western blot. Results ①Compared with the SO group, the serum levels of AMY, ALT, AST, and the hepatocyte AI were significantly increased among the other three groups (P < 0.05). Compared with the SAP group, the serum levels of AMY, ALT, AST, and the hepatocyte AI were significantly decreased in the LY294002 group and rapamycin group (P < 0.05).②Compared with the SO group, the damages of the liver tissues were aggravated among the other three groups. The pathologies of the liver tissues were ameliorated in the LY294002 group and rapamycin group as compared with the SAP group.③Compared with the SO group, the levels of p-Akt/Akt, p-mTOR/mTOR were significantly increased among the other three groups (P < 0.05). Compared with the SAP group, the levels of p-Akt/Akt, p-mTOR/mTOR were significantly decreased in the LY294002 group (P < 0.05), but in the rapamycin group, only the p-mTOR/mTOR level was significantly decreased (P < 0.05). Conclusion The activation of PI3K/Akt/mTOR signaling pathway might be one of the reasons for the liver injury induced by SAP and blocking this signaling pathway might be a potential target of preventing progress of SAP and alleviating liver injury induced by SAP.

Citation： OUYANGJun, ZHOUYue-xian, LIXi, ZHANGZhao-hui, NIUWan-cheng. Role of PI3K/Akt/mTOR Signaling Pathway in Liver Injury Induced by Severe Acute Pancreatitis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(5): 555-559. doi: 10.7507/1007-9424.20150148 Copy

1.	Roberts SE, Akbari A, Thorne K, et al. The incidence of acute pancreatitis:impact of social deprivation, alcohol consumption, seasonal and demographic factors. Aliment Pharmacol Ther, 2013, 38(5):539-548.
2.	Sah RP, Dawra RK, Saluja AK. New insights into the pathogenesis of pancreatitis. Curr Opin Gastroenterol, 2013, 29(5):523-530.
3.	Li ZT, Ma B, Lu M, et al. Construction of network for protein kinases that play a role in acute pancreatitis. Pancreas, 2013, 42(4):607-613.
4.	Xu P, Wang J, Yang ZW, et al. Regulatory roles of the PI3K/Akt signaling pathway in rats with severe acute pancreatitis. PLoS One, 2013, 8(11):e81767.
5.	Working Party of the British Society of Gastroenterology. Association of surgeons of Great Britain and Ireland; pancreatic society of Great Britain and Ireland; association of upper GI surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut, 2005, 54(suppl 3):1-9.
6.	徐延钧, 吴新民, 郭亚民.肿瘤坏死因子-α及白介素在急性胰腺炎中的作用.中国普外基础与临床杂志, 2010, 17(9):993-996.
7.	石力, 田伏洲, 李旭, 等.急性胰腺炎大鼠肝脏NF-κB对TNF-α表达的调控及其在肝损伤中的作用.中国普外基础与临床杂志, 2004, 11(3):228-230.
8.	余文, 吴伟, 张少辉, 等.急性胰腺炎发病机理的研究进展.中国普外基础与临床杂志, 2006, 13(6):733-736.
9.	Sharma B, Srivastava S, Singh N, et al. Role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis:a double-blind randomized controlled trial. J Clin Gastroenterol, 2011, 45(5):442-448.
10.	王峰.异甘草酸镁在大鼠胰腺炎肝损害治疗中的作用.中国药物与临床, 2014, 14(2):180-182.
11.	Halonen KI, Pettila V, Leppaniemi AK, et al. Multiple organ dysfunction associated with severe acute pancreatitis. Crit Care Med, 2002, 30(6):1274-1279.
12.	陈勇, 曾艳凌, 林志辉, 等.早期肝功能损害对急性胰腺炎病因判定的临床价值.世界华人消化杂志, 2012, 20(34):3390-3393.
13.	Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(2):274-293.
14.	Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs. Oncotarget, 2010, 1(7):530-543.
15.	Zhan YH, Liu J, Qu XJ, et al.β-elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/mTOR signalling pathways. Asian Pac J Cancer Prev, 2012, 13(6):2739-2744.
16.	Klempner SJ, Myers AP, Li J, et al. Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. Cancer Res, 2013, 73(8 Supplement):4265.
17.	Dienstmann R, Rodon J, Serra V, et al. Picking the point of inhibition:a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther, 2014, 13(5):1021-1031.
18.	Chen ZH, Yang L, Liu Y, et al. LY294002 and rapamycin promote coxsackievirus-induced cytopathic effect and apoptosis via inhibition of PI3K/AKT/mTOR signaling pathway. Mol Cell Biochem, 2014, 385(1/2):169-177.
19.	Fan QW, Weiss WA. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. Methods Mol Biol, 2012, 821:349-359.
20.	程飞, 张献全, 宋孟龙, 等. P13K/Akt/mTOR信号通路参与缺氧诱导因子-1α在急性胰腺炎大鼠的表达调节.中国急救医学, 2010, 30(4):330-334.
21.	Agani F, Jiang BH. Oxygen-independent regulation of HIF-1:novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets, 2013, 13(3):245-251.
22.	Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology, 2009, 24(2):97-106.
23.	Dos Santos S, Delattre AI, De Longueville F, et al. Gene expression profiling of LPS-stimulated murine macrophages and role of the NF-kappaB and PI3K/mTOR signaling pathways. Ann N Y Acad Sci, 2007, 1096(1):70-77.
24.	Carden CP, Stewart A, Thavasu P, et al. The association of PI3 kinase signaling and chemoresistance in advanced ovarian cancer. Mol Cancer Therapeu, 2012, 11(7):1609-1617.
25.	Cerniglia GJ, Karar J, Tyagi SA, et al. Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-Kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol, 2012, 82(6):1230-1240.
26.	Park KR, Nam D, Yun HM, et al. beta-caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett, 2011, 312(2):178-188.

1. Roberts SE, Akbari A, Thorne K, et al. The incidence of acute pancreatitis:impact of social deprivation, alcohol consumption, seasonal and demographic factors. Aliment Pharmacol Ther, 2013, 38(5):539-548.
2. Sah RP, Dawra RK, Saluja AK. New insights into the pathogenesis of pancreatitis. Curr Opin Gastroenterol, 2013, 29(5):523-530.
3. Li ZT, Ma B, Lu M, et al. Construction of network for protein kinases that play a role in acute pancreatitis. Pancreas, 2013, 42(4):607-613.
4. Xu P, Wang J, Yang ZW, et al. Regulatory roles of the PI3K/Akt signaling pathway in rats with severe acute pancreatitis. PLoS One, 2013, 8(11):e81767.
5. Working Party of the British Society of Gastroenterology. Association of surgeons of Great Britain and Ireland; pancreatic society of Great Britain and Ireland; association of upper GI surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut, 2005, 54(suppl 3):1-9.
6. 徐延钧, 吴新民, 郭亚民.肿瘤坏死因子-α及白介素在急性胰腺炎中的作用.中国普外基础与临床杂志, 2010, 17(9):993-996.
7. 石力, 田伏洲, 李旭, 等.急性胰腺炎大鼠肝脏NF-κB对TNF-α表达的调控及其在肝损伤中的作用.中国普外基础与临床杂志, 2004, 11(3):228-230.
8. 余文, 吴伟, 张少辉, 等.急性胰腺炎发病机理的研究进展.中国普外基础与临床杂志, 2006, 13(6):733-736.
9. Sharma B, Srivastava S, Singh N, et al. Role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis:a double-blind randomized controlled trial. J Clin Gastroenterol, 2011, 45(5):442-448.
10. 王峰.异甘草酸镁在大鼠胰腺炎肝损害治疗中的作用.中国药物与临床, 2014, 14(2):180-182.
11. Halonen KI, Pettila V, Leppaniemi AK, et al. Multiple organ dysfunction associated with severe acute pancreatitis. Crit Care Med, 2002, 30(6):1274-1279.
12. 陈勇, 曾艳凌, 林志辉, 等.早期肝功能损害对急性胰腺炎病因判定的临床价值.世界华人消化杂志, 2012, 20(34):3390-3393.
13. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(2):274-293.
14. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs. Oncotarget, 2010, 1(7):530-543.
15. Zhan YH, Liu J, Qu XJ, et al.β-elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/mTOR signalling pathways. Asian Pac J Cancer Prev, 2012, 13(6):2739-2744.
16. Klempner SJ, Myers AP, Li J, et al. Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. Cancer Res, 2013, 73(8 Supplement):4265.
17. Dienstmann R, Rodon J, Serra V, et al. Picking the point of inhibition:a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther, 2014, 13(5):1021-1031.
18. Chen ZH, Yang L, Liu Y, et al. LY294002 and rapamycin promote coxsackievirus-induced cytopathic effect and apoptosis via inhibition of PI3K/AKT/mTOR signaling pathway. Mol Cell Biochem, 2014, 385(1/2):169-177.
19. Fan QW, Weiss WA. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. Methods Mol Biol, 2012, 821:349-359.
20. 程飞, 张献全, 宋孟龙, 等. P13K/Akt/mTOR信号通路参与缺氧诱导因子-1α在急性胰腺炎大鼠的表达调节.中国急救医学, 2010, 30(4):330-334.
21. Agani F, Jiang BH. Oxygen-independent regulation of HIF-1:novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets, 2013, 13(3):245-251.
22. Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology, 2009, 24(2):97-106.
23. Dos Santos S, Delattre AI, De Longueville F, et al. Gene expression profiling of LPS-stimulated murine macrophages and role of the NF-kappaB and PI3K/mTOR signaling pathways. Ann N Y Acad Sci, 2007, 1096(1):70-77.
24. Carden CP, Stewart A, Thavasu P, et al. The association of PI3 kinase signaling and chemoresistance in advanced ovarian cancer. Mol Cancer Therapeu, 2012, 11(7):1609-1617.
25. Cerniglia GJ, Karar J, Tyagi SA, et al. Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-Kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol, 2012, 82(6):1230-1240.
26. Park KR, Nam D, Yun HM, et al. beta-caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett, 2011, 312(2):178-188.

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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Role of PI3K/Akt/mTOR Signaling Pathway in Liver Injury Induced by Severe Acute Pancreatitis

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