Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Ursodeoxycholic Acid (UDCA) Reduces Hepatocyte Apoptosis by Inhibiting Farnesoid X Receptor (FXR) in Hemorrhagic Shock (HS)

Author(s): Lu Wang, Xi Rui, Huai-Wu He, Xiang Zhou* and Yun Long*

Volume 23, Issue 6, 2023

Published on: 05 August, 2022

Page: [550 - 558] Pages: 9

DOI: 10.2174/1566524022666220525152811

Price: $65

Abstract

Background: Hemorrhagic shock (HS) is the most common cause of potentially preventable death after traumatic injury. Acute liver injury is an important manifestation of HS. Apoptosis plays an important role in liver injury. Farnesoid X receptor (FXR) can alleviate liver injury. This study aimed to examine the effects of ursodeoxycholic acid (UDCA) on hepatocyte apoptosis in HS and its relationship with the FXR pathway.

Methods: Mice were randomly divided into 4 groups: sham group, HS group, HS + UDCA group, and FXR (-) + HS + UDCA group. There were 6 mice in each group. As to the model of HS, MAP of 40 ± 5 mmHg was maintained for 1 hour. As to UDCA intervention, UDCA (300mg/kg) was given nasally. Real-time RT-PCR and Western blotting were used to detect changes in the expression level of Caspase-3, Bax, LC3Ⅰ, LC3Ⅱ, Bcl-2, and Beclin-1 in the liver. TUNEL assay was used to detect changes in hepatocyte apoptosis.

Results: The expression level of Caspase-3 and Bax in the liver decreased significantly after treatment with UDCA under HS conditions. The expression level of LC3Ⅰ, LC3Ⅱ, Bcl-2, and Beclin-1 in the liver increased significantly after treatment with UDCA under HS conditions. TUNEL positive percentage of liver decreased significantly after treatment with UDCA under HS conditions. In the case of FXR (-), the influence of UDCA was inhibited.

Conclusion: These results indicated that UDCA could reduce hepatocyte apoptosis during HS through the FXR pathway.

Keywords: Ursodeoxycholic acid, hepatocyte apoptosis, farnesoid X receptor, hemorrhagic shock, liver injury, trauma.

« Previous Next »
[1]
Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: An overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60(6) (Suppl.): S3-S11.
[http://dx.doi.org/10.1097/01.ta.0000199961.02677.19] [PMID: 16763478]
[2]
Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: A reassessment. J Trauma 1995; 38(2): 185-93.
[http://dx.doi.org/10.1097/00005373-199502000-00006] [PMID: 7869433]
[3]
Senosiain Lalastra C, Arribas Anta J, Moreira Vicente V, et al. Acute liver ischaemia after gastro-oesophageal variceal bleeding. Gastroenterol Hepatol 2016; 39(9): 590-6.
[http://dx.doi.org/10.1016/j.gastrohep.2016.03.007] [PMID: 27112800]
[4]
Ko SF, Chen YL, Sung PH, et al. Hepatic 31 P-magnetic resonance spectroscopy identified the impact of melatonin-pretreated mitochondria in acute liver ischaemia-reperfusion injury. J Cell Mol Med 2020; 24(17): 10088-99.
[http://dx.doi.org/10.1111/jcmm.15617] [PMID: 32691975]
[5]
Iorga A, Dara L, Kaplowitz N. Drug-induced liver injury: Cascade of events leading to cell death, apoptosis or necrosis. Int J Mol Sci 2017; 18(5): E1018.
[http://dx.doi.org/10.3390/ijms18051018] [PMID: 28486401]
[6]
Liu H, Li Q, Wang Y, Hong H, Chen M, Hong F, et al. Elevated nitric oxide levels associated with hepatic cell apoptosis during liver injury. Hepatol Res 2017; 47(2): 178-85.
[http://dx.doi.org/10.1111/hepr.12783]
[7]
Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited. Hepatology 2002; 36(3): 525-31.
[http://dx.doi.org/10.1053/jhep.2002.36088] [PMID: 12198643]
[8]
Ordonez R, Carbajo-Pescador S, Mauriz JL, Gonzalez-Gallego J. Understanding nutritional interventions and physical exercise in non-alcoholic fatty liver disease. Curr Mol Med 2015; 15(1): 3-26.
[http://dx.doi.org/10.2174/1566524015666150114110551] [PMID: 25601465]
[9]
Han CY, Rho HS, Kim A, et al. FXR inhibits endoplasmic reticulum stress-induced NLRP3 inflammasome in hepatocytes and ameliorates liver injury. Cell Rep 2018; 24(11): 2985-99.
[http://dx.doi.org/10.1016/j.celrep.2018.07.068] [PMID: 30208322]
[10]
Iracheta-Vellve A, Calenda CD, Petrasek J, et al. FXR and TGR5 agonists ameliorate liver injury, steatosis, and inflammation after binge or prolonged alcohol feeding in mice. Hepatol Commun 2018; 2(11): 1379-91.
[http://dx.doi.org/10.1002/hep4.1256] [PMID: 30411084]
[11]
Wang H, Ge C, Zhou J, et al. Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis. EBioMedicine 2018; 37: 322-33.
[http://dx.doi.org/10.1016/j.ebiom.2018.10.028] [PMID: 30337250]
[12]
Kao RL, Xu X, Xenocostas A, et al. Induction of acute lung inflammation in mice with hemorrhagic shock and resuscitation: Role of HMGB1. J Inflamm 2014; 11(1): 30.
[http://dx.doi.org/10.1186/s12950-014-0030-7] [PMID: 25309129]
[13]
Chung YR, Choi JA, Koh JY, Yoon YH. Ursodeoxycholic acid attenuates endoplasmic reticulum stress-related retinal pericyte loss in streptozotocin-induced diabetic mice. J Diabetes Res 2017; 2017: 1763292.
[http://dx.doi.org/10.1155/2017/1763292] [PMID: 28127564]
[14]
Woo SJ, Kim JH, Yu HG. Ursodeoxycholic acid and tauroursodeoxycholic acid suppress choroidal neovascularization in a laser-treated rat model. J Ocul Pharmacol Ther 2010; 26(3): 223-9.
[http://dx.doi.org/10.1089/jop.2010.0012] [PMID: 20565307]
[15]
Fan TJ, Han LH, Cong RS, Liang J. Caspase family proteases and apoptosis. Acta Biochim Biophys Sin 2005; 37(11): 719-27.
[http://dx.doi.org/10.1111/j.1745-7270.2005.00108.x] [PMID: 16270150]
[16]
Khalilzadeh B, Shadjou N, Kanberoglu GS, et al. Advances in nanomaterial based optical biosensing and bioimaging of apoptosis via caspase-3 activity: A review. Mikrochim Acta 2018; 185(9): 434.
[http://dx.doi.org/10.1007/s00604-018-2980-6] [PMID: 30159750]
[17]
Liu H, Li S, Jiang W, Li Y. MiR-484 Protects Rat Myocardial Cells from Ischemia-Reperfusion Injury by Inhibiting Caspase-3 and Caspase-9 during Apoptosis. Korean Circ J 2020; 50(3): 250-63.
[http://dx.doi.org/10.4070/kcj.2019.0107] [PMID: 31845557]
[18]
Wu Y, Chen W, Zhang Y, et al. Potent therapy and transcriptional profile of combined erythropoietin-derived peptide cyclic helix B surface peptide and caspase-3 siRNA against kidney ischemia/reperfusion injury in mice. J Pharmacol Exp Ther 2020; 375(1): 92-103.
[http://dx.doi.org/10.1124/jpet.120.000092] [PMID: 32759272]
[19]
Jiang Y, Fang B, Xu B, Chen L. The RAS-PI3K-AKT-NF-κB pathway transcriptionally regulates the expression of BCL2 family and IAP family genes and inhibits apoptosis in fibrous epulis. J Clin Lab Anal 2020; 34(3): e23102.
[http://dx.doi.org/10.1002/jcla.23102] [PMID: 31743516]
[20]
Edlich F. BCL-2 proteins and apoptosis: Recent insights and unknowns. Biochem Biophys Res Commun 2018; 500(1): 26-34.
[http://dx.doi.org/10.1016/j.bbrc.2017.06.190] [PMID: 28676391]
[21]
Hu L, Chen M, Chen X, et al. Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell Death Dis 2020; 11(4): 281.
[http://dx.doi.org/10.1038/s41419-020-2476-2] [PMID: 32332857]
[22]
Matsuzawa-Ishimoto Y, Hwang S, Cadwell K. Autophagy and Inflammation. Annu Rev Immunol 2018; 36: 73-101.
[http://dx.doi.org/10.1146/annurev-immunol-042617-053253] [PMID: 29144836]
[23]
Houtman J, Freitag K, Gimber N, Schmoranzer J, Heppner FL, Jendrach M. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3. EMBO J 2019; 38(4): e99430.
[http://dx.doi.org/10.15252/embj.201899430] [PMID: 30617086]
[24]
Heckmann BL, Green DR. LC3-associated phagocytosis at a glance. J Cell Sci 2019; 132(5): jcs222984.
[25]
Crowley LC, Marfell BJ, Waterhouse NJ. Detection of DNA fragmentation in apoptotic cells by TUNEL. Cold Spring Harb Protoc 2016; 2016(10): pdb-rot087221.
[http://dx.doi.org/10.1101/pdb.prot087221] [PMID: 27698233]
[26]
Borude P, Edwards G, Walesky C, et al. Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology 2012; 56(6): 2344-52.
[http://dx.doi.org/10.1002/hep.25918] [PMID: 22730081]
[27]
Fujino T, Maruko-Ohtake A, Ohtake Y, et al. Farnesoid X receptor knockdown provides significant growth inhibition in hepatocellular carcinoma cells while it does not interfere with the proliferation of primary human hepatocyte-derived cells. J Toxicol Sci 2015; 40(4): 501-8.
[http://dx.doi.org/10.2131/jts.40.501] [PMID: 26165647]
[28]
Dong R, Wang X, Wang L, et al. Yangonin inhibits ethanol-induced hepatocyte senescence via miR-194/FXR axis. Eur J Pharmacol 2021; 890: 173653.
[http://dx.doi.org/10.1016/j.ejphar.2020.173653] [PMID: 33068587]
[29]
Vaquero J, Briz O, Herraez E, Muntané J, Marin JJ. Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta 2013; 1833(10): 2212-9.
[http://dx.doi.org/10.1016/j.bbamcr.2013.05.006] [PMID: 23680185]

Rights & Permissions Print Cite
Article Metrics
4
© 2024 Bentham Science Publishers | Privacy Policy