Protective effect of 4-phenylbutyric acid on severe acute pancreatitis-induced liver injury in rats_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HONGYupu ^1,2 , GUOWenyi ¹ , ZHAOLiang ^1,2 , DENGWenhong ¹ , XIANGMingwei ^1,2 , YUJia ¹ , ZHOUYu ^1,2 ,  WANGWeixing ¹

1. Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;
2. Key Laboratory of Hubei Province for Digestive System Disease, Wuhan 430060, P. R. China;

Corresponding author：

WANGWeixing, Email: sate.llite@163.com

Keywords：

acute pancreatitis; endoplasmic reticulum stress; liver injury; cell apotosis; 4-phenylbutyric acid

DOI：

10.7507/1007-9424.201605067

Video：

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Objective To investigate the protective effect of 4-phenylbutyric acid (PBA) on liver injury induced by severe acute pancreatitis (SAP) in rats and its possible mechanism. Methods Twenty-four SPF adult male Sprague Dawley rats were randomly divided into three groups: shame operation group (SO group,n=8), SAP group (n=8), and PBA group (n=8). SAP model was induced by retrograde injection of 5% sodium taurocholate (1 mL/kg) in biliopancreatic duct in SAP group and PBA group. PBA solution (50 mg/kg) was administeredvia intraperitoneal injection for 3 days prior to establishing models in PBA group. Rats were injected equivalent saline solution instead of PBA solution in SAP group and SO group. All rats were sacrificed at 12 h after modeling. Blood samples were collected by inferior vena cava puncture, and serum levels of amylase (AMY), alanine aminotransferase (ALT), and aspartate transaminase (AST) were measured using a fully automatic chemistry analyzer. The head of pancreas and right lobe of hepatic tissues were harvested and pathological examination was observed under the light microscope. Expressions of glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and Caspase-3 in hepatic tissues were evaluated by immunohistochemistry assay. Results Compared with SO group, the serum levels of AMY, ALT and AST were significantly increased in SAP group (P＜0.05). The serum levels of ALT and AST in PBA group were significantly lower than those in SAP group (P＜0.05). There was no difference of the serum levels of AMY between in PBA group and SAP group (P＞0.05). Compared with SO group, the damages of the pancreas and liver tissues and the expressions of GRP78, CHOP and Caspase-3 in hepatic tissues were significantly increased in SAP group (P＜0.05). And the above indices in PBA group were significantly decreased when compared with SAP group. Conclusions PBA can alleviate severe acute pancreatitis-induced liver injury, and the mechanism may be associated with inhibition of endoplasmic reticulum stress (ERS) and reduction of hepatocyte apoptosis.

Citation： HONGYupu, GUOWenyi, ZHAOLiang, DENGWenhong, XIANGMingwei, YUJia, ZHOUYu, WANGWeixing. Protective effect of 4-phenylbutyric acid on severe acute pancreatitis-induced liver injury in rats. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(1): 18-23. doi: 10.7507/1007-9424.201605067 Copy

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2.	Wu JS, Li WM, Chen YN,et al. Endoplasmic reticulum stress is activated in acute pancreatitis. J Dig Dis, 2016, 17(5): 295-303.
3.	李杨, 赵鹏, 苏春, 等. 内质网应激在大鼠重症急性胰腺炎肝损伤的临床意义. 检验医学与临床, 2015, 12(12): 1720-1722.
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5.	Koyama M, Furuhashi M, Ishimura S,et al. Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol, 2014, 306(9): H1314-H1323.
6.	He X, Yu J, Guo W,et al. Effects of thymosin beta4 on a rat model of severe acute pancreatitis. Exp Ther Med, 2015, 10(6): 2389-2395.
7.	Yao Z, Guo Z, Yang C,et al. Phenylbutyric acid prevents rats from electroconvulsion-induced memory deficit with alterations of memory-related proteins and tau hyperphosphorylation. Neuroscience, 2010, 168(2): 405-415.
8.	Schmidt J, Rattner DW, Lewandrowski K,et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg, 1992, 215(1): 44-56.
9.	Camargo CA Jr, Madden JF, Gao W,et al. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology, 1997, 26(6): 1513-1520.
10.	Wang P, Shi Q, Deng WH,et al. Relationship between expression of NADPH oxidase 2 and invasion and prognosis of human gastric cancer. World J Gastroenterol, 2015, 21(20): 6271-6279.
11.	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.
12.	Lv P, Fan LJ, Li HY,et al. Protective effect of thalidomide on liver injury in rats with acute pancreatitis via inhibition of oxidative stress. Ann Clin Lab Sci, 2015, 45(5): 508-514.
13.	李春生, 蔡雷, 王银平, 等. COX-2在重症急性胰腺炎所致肝脏损伤中的作用. 中国普外基础与临床杂志, 2010, 17(4): 343-347.
14.	欧阳军, 周跃鲜, 李玺, 等. PI3K/Akt/mTI3K/Akt/mOR信号通路在重症急性胰腺炎致肝脏损伤中的作用. 中国普外基础与临床杂志, 2015, 22(5): 555-559.
15.	邓文宏, 郭闻一, 陈辰, 等. 花姜酮对重症急性胰腺炎大鼠肝损伤的保护作用及机制. 中华实验外科杂志, 2015, 32(1): 37-40.
16.	Cao SS, Kaufman RJ. Unfolded protein response. Current biology, 2012, 22(16): R622-626.
17.	Cao SS, Luo KL, Shi L. Endoplasmic reticulum stress interacts with inflammation in human diseases. J Cell Physiol, 2016, 231(2): 288-294.
18.	Rao J, Zhang C, Wang P,et al. C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1alpha signalling in acute liver failure. Biochem J, 2015, 466 (2): 369-378.
19.	Li X, Wang Y, Wang H,et al. Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis. Inflamm Res, 2015, 64(1): 1-7.
20.	Ren F, Zhou L, Zhang X,et al. Endoplasmic reticulum stress-activated glycogen synthase kinase 3beta aggravates liver inflammation and hepatotoxicity in mice with acute liver failure. Inflammation, 2015, 38(3): 1151-1165.
21.	Yao X, Li Y, Cheng X,et al. ER stress contributes to alpha-naphthyl isothiocyanate-induced liver injury with cholestasis in mice. Pathol Res Pract, 2016, 212(6): 560-567.
22.	Ren F, Shi H, Zhang L,et al. The dysregulation of endoplasmic reticulum stress response in acute-on-chronic liver failure patients caused by acute exacerbation of chronic hepatitis B. J Viral Hepat, 2016, 23(1): 23-31.
23.	Wu FL, Liu WY, Van Poucke S,et al. Targeting endoplasmic reticulum stress in liver disease. Expert Rev Gastroenterol Hepatol, 2016, 10(9): 1041-1052.
24.	Carlisle RE, Brimble E, Werner KE,et al. 4-Phenylbutyrate inhibits tunicamycin-induced acute kidney injury via CHOP/GADD153 repression. PLoS One, 2014, 9(1): e84663.
25.	Yang J, Fier A, Carter Y,et al. Liver injury during acute pancreatitis: the role of pancreatitis-associated ascitic fluid (PAAF), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis. J Gastrointest Surg, 2003, 7(2): 200-207; discussion 208.
26.	Mimori S, Okuma Y, Kaneko M,et al. Protective effects of 4-phenylbutyrate derivatives on the neuronal cell death and endoplasmic reticulum stress. Biol Pharm Bull, 2012, 35(1): 84-90.
27.	Ayala P, Montenegro J, Vivar R,et al. Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Exp Mol Pathol, 2012, 92(1): 97-104.

1. Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J, 2016, 283(14): 2640-2652.
2. Wu JS, Li WM, Chen YN,et al. Endoplasmic reticulum stress is activated in acute pancreatitis. J Dig Dis, 2016, 17(5): 295-303.
3. 李杨, 赵鹏, 苏春, 等. 内质网应激在大鼠重症急性胰腺炎肝损伤的临床意义. 检验医学与临床, 2015, 12(12): 1720-1722.
4. Lichter-Konecki U, Diaz GA, Merritt JL 2nd,et al. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab, 2011, 103(4): 323-329.
5. Koyama M, Furuhashi M, Ishimura S,et al. Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol, 2014, 306(9): H1314-H1323.
6. He X, Yu J, Guo W,et al. Effects of thymosin beta4 on a rat model of severe acute pancreatitis. Exp Ther Med, 2015, 10(6): 2389-2395.
7. Yao Z, Guo Z, Yang C,et al. Phenylbutyric acid prevents rats from electroconvulsion-induced memory deficit with alterations of memory-related proteins and tau hyperphosphorylation. Neuroscience, 2010, 168(2): 405-415.
8. Schmidt J, Rattner DW, Lewandrowski K,et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg, 1992, 215(1): 44-56.
9. Camargo CA Jr, Madden JF, Gao W,et al. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology, 1997, 26(6): 1513-1520.
10. Wang P, Shi Q, Deng WH,et al. Relationship between expression of NADPH oxidase 2 and invasion and prognosis of human gastric cancer. World J Gastroenterol, 2015, 21(20): 6271-6279.
11. 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.
12. Lv P, Fan LJ, Li HY,et al. Protective effect of thalidomide on liver injury in rats with acute pancreatitis via inhibition of oxidative stress. Ann Clin Lab Sci, 2015, 45(5): 508-514.
13. 李春生, 蔡雷, 王银平, 等. COX-2在重症急性胰腺炎所致肝脏损伤中的作用. 中国普外基础与临床杂志, 2010, 17(4): 343-347.
14. 欧阳军, 周跃鲜, 李玺, 等. PI3K/Akt/mTI3K/Akt/mOR信号通路在重症急性胰腺炎致肝脏损伤中的作用. 中国普外基础与临床杂志, 2015, 22(5): 555-559.
15. 邓文宏, 郭闻一, 陈辰, 等. 花姜酮对重症急性胰腺炎大鼠肝损伤的保护作用及机制. 中华实验外科杂志, 2015, 32(1): 37-40.
16. Cao SS, Kaufman RJ. Unfolded protein response. Current biology, 2012, 22(16): R622-626.
17. Cao SS, Luo KL, Shi L. Endoplasmic reticulum stress interacts with inflammation in human diseases. J Cell Physiol, 2016, 231(2): 288-294.
18. Rao J, Zhang C, Wang P,et al. C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1alpha signalling in acute liver failure. Biochem J, 2015, 466 (2): 369-378.
19. Li X, Wang Y, Wang H,et al. Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis. Inflamm Res, 2015, 64(1): 1-7.
20. Ren F, Zhou L, Zhang X,et al. Endoplasmic reticulum stress-activated glycogen synthase kinase 3beta aggravates liver inflammation and hepatotoxicity in mice with acute liver failure. Inflammation, 2015, 38(3): 1151-1165.
21. Yao X, Li Y, Cheng X,et al. ER stress contributes to alpha-naphthyl isothiocyanate-induced liver injury with cholestasis in mice. Pathol Res Pract, 2016, 212(6): 560-567.
22. Ren F, Shi H, Zhang L,et al. The dysregulation of endoplasmic reticulum stress response in acute-on-chronic liver failure patients caused by acute exacerbation of chronic hepatitis B. J Viral Hepat, 2016, 23(1): 23-31.
23. Wu FL, Liu WY, Van Poucke S,et al. Targeting endoplasmic reticulum stress in liver disease. Expert Rev Gastroenterol Hepatol, 2016, 10(9): 1041-1052.
24. Carlisle RE, Brimble E, Werner KE,et al. 4-Phenylbutyrate inhibits tunicamycin-induced acute kidney injury via CHOP/GADD153 repression. PLoS One, 2014, 9(1): e84663.
25. Yang J, Fier A, Carter Y,et al. Liver injury during acute pancreatitis: the role of pancreatitis-associated ascitic fluid (PAAF), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis. J Gastrointest Surg, 2003, 7(2): 200-207; discussion 208.
26. Mimori S, Okuma Y, Kaneko M,et al. Protective effects of 4-phenylbutyrate derivatives on the neuronal cell death and endoplasmic reticulum stress. Biol Pharm Bull, 2012, 35(1): 84-90.
27. Ayala P, Montenegro J, Vivar R,et al. Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Exp Mol Pathol, 2012, 92(1): 97-104.

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Protective effect of 4-phenylbutyric acid on severe acute pancreatitis-induced liver injury in rats

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