Study on the mechanism of inhibiting liver tissue apoptosis by 4-phenylbutyrate sodium salt and alleviating liver injury in sepsis

FU Jingnan; ZHOU Li

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Medical Journal of the Chinese People Armed Police Forces ›› 2024, Vol. 35 ›› Issue (8) : 667-671.

Study on the mechanism of inhibiting liver tissue apoptosis by 4-phenylbutyrate sodium salt and alleviating liver injury in sepsis

FU Jingnan¹, ZHOU Li²

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Abstract

Objective To investigate the protective effect of 4-phenylbutyrate (4-PBA) on liver apoptosis in septic mice and its signaling mechanism. Methods The mice were randomly divided into 3 groups: Sham operation group (Sham group), sepsis group (model group, LPS group), and experimental group (treatment group, LPS+4-PBA group). At 24h after LPS, the general condition, sepsis severity score, liver function, liver tissue inflammation index and liver tissue apoptosis degree of mice in each group were observed. Western blot was used to detect the expression levels of apoptosis-related proteins Bax, Bcl-2 and endoplasmic reticulum stress-related proteins ATF4 and CHOP. Results The severity scores of sepsis in LPS group and LPS+4-PBA group were significantly higher than those in Sham group, and those in LPS+4-PBA group were lower than those in LPS group (P<0.05). ALT [(395.10±93.08)IU/L] and AST[(625.50±63.68)IU/L], the apoptotic index (0.0209±0.0041), the levels of IL-6(9406±674), TNF-α(822.30±229.10) and IL-1β(10.58±0.14) in LPS group were significantly higher than those in Sham group. After treatment with 4-PBA, the above indexes of septic mice significantly decreased, and the differences were statistically significant (P<0.05). The results of apoptosis level of related proteins in liver tissue of mice in each group showed that the expression of apoptosis-related protein caspase-3 could be significantly reduced after pre-administration of 4-PBA. The results showed that pretreatment with 4-PBA significantly reduced the protein expression of endoplasmic reticulum stress pathway-related proteins ATF-4 and CHOP in liver tissues of septic mice. Conclusions 4-PBA can inhibit the apoptosis of liver tissue in septic mice by inhibiting ATF-4/ CHOP signaling pathway, thus alleviating sepsis-induced liver injury.

Key words

4-PBA / sepsis / endoplasmic reticulum stress / apoptosis of cells

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FU Jingnan, ZHOU Li. Study on the mechanism of inhibiting liver tissue apoptosis by 4-phenylbutyrate sodium salt and alleviating liver injury in sepsis[J]. Medical Journal of the Chinese People Armed Police Forces. 2024, 35(8): 667-671

References

[1] 王桂秋,刘雪萍,邓书武,等.中药治疗急性肝损伤作用机制研究进展[J].广西医科大学学报,2023,40(11):1921-1927.
[2] Vincent J L, Angus D C, Artigas A, et al. Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial[J]. Crit Care Med, 2003,31(3):834-840.
[3] Brun-Buisson C, Meshaka P, Pinton P, et al. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units[J]. Intensive Care Med, 2004,30(4):580-588.
[4] 陈皓,窦琳,杨光,等.肝细胞脂性凋亡在NASH中的作用和机制研究[J].生命的化学, 2020, 40(10): 1730-1737.
[5] Najimi M, Smets F, Sokal E. Hepatocyte apoptosis[J]. Methods Mol Biol, 2009,481:59-74.
[6] 沈炎,许文聪,代海洋,等.细胞死亡机制在肝纤维化中的研究进展[J].中西医结合肝病杂志, 2023, 33(5):456-459.
[7] 陈玮钰,张荣臻,舒发明,等.肝细胞癌中调节性细胞死亡方式研究进展[J].辽宁中医药大学学报, 2023, 25 (7): 89-93.
[8] 张雨欣,周小杰,于浩然,等.内质网应激与氧化应激[J].农业生物技术学报,2022,30(10):2009-2024.
[9] Malhi H, Kaufman R J. Endoplasmic reticulum stress in liver disease[J]. J Hepatol,2011,54(4): 795- 809.
[10] 杨燕丽,向若兰,孙琦,等.4-PBA抗糖尿病大鼠内质网应激作用及机制[J].基础医学与临床, 2016, 36 (6):728-733.
[11] Xia S W, Wang Z M, Sun S M, et al. Endoplasmic reticulum stress and protein degradation in chronic liver disease[J]. Pharmacol Res, 2020,161:105218.
[12] Luo T, Chen B, Wang X. 4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress[J]. Chem Biol Interact, 2015,5;242:99-106.
[13] Ren F, Zhou L, Zhang X, et al. Endoplasmic reticulum stress-activated glycogen synthase kinase 3β aggravates liver inflammation and hepatotoxicity in mice with acute liver failure[J]. Inflammation, 2015,38(3): 1151-1165.
[14] Luo T, Chen B, Wang X. 4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress[J]. Chem Biol Interact,2015,242:99-106.
[15] Maestri N E, Brusilow S W,Clissold D B,et al. Long-term treatment of girls with ornithine transcarbamylase deficiency[J].N Engl J Med,1996,335(12):855-859.
[16] Dover G J,Brusilow S,Charache S.Induction of fatal hemoglobin productionin subjects with sickle cell anemia by oral sodium phenylbutyrate[J].Blood,1994.84(1):339-343.
[17] Nissar A U,Sharma L, Mudasir M A, Nazir L A, et al. Chemical chaperone 4-phenyl butyric acid (4-PBA) reduces hepatocellular lipid accumulation and lipotoxicity through induction of autophagy[J]. J Lipid Res,2017,58(9):1855-1868.
[18] Zuo L, Zhu Y, Hu L,et al. PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1α/Calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC Activation[J]. J Cell Mol Med, 2019,23(6):3940-3950.
[19] Liu J, Han P, Li M, et al. Histidine-rich calcium binding protein promotes growth of hepatocellular carcinoma in vitro and in vivo[J]. Cancer Sci,2015,106(10):1288-1295.
[20] Ozcan U, Yilmaz E, Ozcan L, et al.Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes[J].Science, 2006,313(5790):1137-1140.
[21] Luo Z F, Feng B, Mu J, et al. Effects of 4-phenylbutyric acid on the process and development of diabetic nephropathy induced in rats by streptozotocin:regulation of endoplasmic reticulum stress-oxidative activation[J]. Toxicol Appl Pharmacol,2010,246(1-2):49-57.
[22] Vilatoba M, Eckstein C, Bilbao G,et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis[J].Surgery, 2005,138(2):342-351.
[23] Qi X, Hosoi T, Okuma Y, et al.Sodium 4-phenylbutyrate protects against cerebral ischemic injury [J].Mol Pharmacol, 2004,66(4):899-908.
[24] Mizukami T, Orihashi K, Herlambang B, et al. Sodium 4-phenylbutyrate protects against spinal cord ischemia by inhibition of endoplasmic reticulum stress[J].J Vasc Surg,2010,52(6):1580-1586.
[25] Malo A, Kruger B, Goke B, et al.4-Phenylbutyric acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini[J]. Pancreas, 2013, 42: 92-101.
[26] Malo A, Kruger B, Goke B, et al.4-Phenylbutyric acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini[J]. Pancreas, 2013, 42: 92-101.
[27] 马丽,肖敏,董良.内质网应激在急性肺损伤中的研究进展[J].临床与病理杂志, 2022, 42 (3): 744-749.
[28] 王安琪,孙国平.内质网应激在抗肿瘤治疗中的作用及研究进展[J].中国药理学通报, 2021, 37(12): 1643-1647.
[29] 张勇涛,李霞,李晓齐,等.内质网应激通路相关蛋白IRE1、PERK、ATF6在舌鳞癌中的表达及其功能的生物信息学分析[J].生物化工, 2023,9(5):1-6,18.