Sestrin2 protects against cholestatic liver injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-mediated pyroptosis
1
조회
0
다운로드
2
인용
0
참고문헌
초록
Chronic exposure to bile acid in the liver due to impaired bile flow induces cholestatic liver disease, resulting in hepatotoxicity and liver fibrosis. Sestrin2, a highly conserved, stress-inducible protein, has been implicated in cellular responses to multiple stress conditions and the maintenance of cellular homeostasis. However, its role in cholestatic liver injury is not fully understood. In this study, we investigated the role of hepatic Sestrin2 in cholestatic liver injury and its underlying mechanisms using in vivo and in vitro approaches. Hepatic Sestrin2 expression was upregulated by activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-β (C/EBP-β) after treatment with bile acids and correlated with endoplasmic reticulum (ER) stress responses. Bile-duct ligation (BDL)-induced hepatocellular apoptosis and liver fibrosis were exacerbated in Sestrin2-knockout (Sesn2−/−) mice. Moreover, Sestrin2 deficiency enhanced cholestasis-induced hepatic ER stress, whereas Sestrin2 overexpression ameliorated bile acid-induced ER stress. Notably, the mammalian target of rapamycin (mTOR) inhibitor rapamycin and the AMP-activated protein kinase (AMPK) activator AICAR reversed bile acid-induced ER stress in Sestrin2-deficient cells. Furthermore, Sestrin2 deficiency promoted cholestasis-induced hepatic pyroptosis by activating NLRP3 inflammasomes. Thus, our study provides evidence for the biological significance of Sestrin2 and its relationship with cholestatic liver injury, suggesting the potential role of Sestrin2 in regulating ER stress and inflammasome activation during cholestatic liver injury.
Abstract
Chronic exposure to bile acid in the liver due to impaired bile flow induces cholestatic liver disease, resulting in hepatotoxicity and liver fibrosis. Sestrin2, a highly conserved, stress-inducible protein, has been implicated in cellular responses to multiple stress conditions and the maintenance of cellular homeostasis. However, its role in cholestatic liver injury is not fully understood. In this study, we investigated the role of hepatic Sestrin2 in cholestatic liver injury and its underlying mechanisms using in vivo and in vitro approaches. Hepatic Sestrin2 expression was upregulated by activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-β (C/EBP-β) after treatment with bile acids and correlated with endoplasmic reticulum (ER) stress responses. Bile-duct ligation (BDL)-induced hepatocellular apoptosis and liver fibrosis were exacerbated in Sestrin2-knockout (Sesn2−/−) mice. Moreover, Sestrin2 deficiency enhanced cholestasis-induced hepatic ER stress, whereas Sestrin2 overexpression ameliorated bile acid-induced ER stress. Notably, the mammalian target of rapamycin (mTOR) inhibitor rapamycin and the AMP-activated protein kinase (AMPK) activator AICAR reversed bile acid-induced ER stress in Sestrin2-deficient cells. Furthermore, Sestrin2 deficiency promoted cholestasis-induced hepatic pyroptosis by activating NLRP3 inflammasomes. Thus, our study provides evidence for the biological significance of Sestrin2 and its relationship with cholestatic liver injury, suggesting the potential role of Sestrin2 in regulating ER stress and inflammasome activation during cholestatic liver injury.
참고문헌 (59)
- Li, T., "Bile acids as metabolic regulators", Curr. Opin. Gastroenterol, 31, pp.159~165 (2015)
- Haenel, L. C., "Thrombophlebitis complicating sternocostoclavicular hyperostosis", Postgrad. Med, 68, pp.113~115 (1980)[DOI]
- Zollner, G., "Mechanisms of cholestasis", Clin. Liver Dis, 12, pp.1~26 (2008)[DOI]
- Li, T., "Bile acid metabolism and signaling in cholestasis, inflammation, and cancer", Adv. Pharm, 74, pp.263~302 (2015)
- Kim, S., "Impaired autophagy promotes bile acid-induced hepatic injury and accumulation of ubiquitinated proteins", Biochem. Biophys. Res. Commun, 495, pp.1541~1547 (2018)
- Malhi, H., "Endoplasmic reticulum stress in liver disease", J. Hepatol, 54, pp.795~809 (2011)
- Park, H. W., "Hepatoprotective role of Sestrin2 against chronic ER stress", Nat. Commun, 5, pp.4233~ (2014)
- Henkel, A. S., "Endoplasmic reticulum stress regulates hepatic bile acid metabolism in mice", Cell. Mol. Gastroenterol. Hepatol, 3, pp.261~271 (2017)
- Zhu, J., "Salvianolic acid A attenuates endoplasmic reticulum stress and protects against cholestasis-induced liver fibrosis via the SIRT1", HSF1 pathway, 2018, pp.9, 1277~
- Robin, M. J., "Calnexin depletion by endoplasmic reticulum stress during cholestasis inhibits the Na(+)-taurocholate cotransporting polypeptide", Hepatol. Commun, 2, pp.1550~1566 (2018)
- Gu, Y., "Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme", Science, 275, pp.206~209 (1997)
- Heneka, M. T., "Inflammasome signalling in brain function and neurodegenerative disease", Nat. Rev. Neurosci, 19, pp.610~621 (2018)
- Latz, E., "The inflammasomes : mechanisms of activation and function", Curr. Opin. Immunol, 22, pp.28~33 (2010)
- Lamkanfi, M., "Inflammasomes and their roles in health and disease", Annu. Rev. Cell Dev. Biol, 28, pp.137~161 (2012)
- Gong, Z., "Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis", Oncotarget, 7, pp.83951~83963 (2016)
- Frissen, M., "Bidirectional role of NLRP3 during acute and chronic cholestatic liver injury", Hepatology, 73, pp.1836~1854 (2021)
- Budanov, A. V., "Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling", Antioxid. Redox Signal, 15, pp.1679~1690 (2011)
- Lee, J. H., "Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies", Science, 327, pp.1223~1228 (2010)
- Lee, J. H., "Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3", Cell Metab, 16, pp.311~321 (2012)
- Lee, S., "Sestrin2 alleviates palmitate-induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells", Am. J. Reprod. Immunol, 83, pp.e13222~ (2020)
- Shin, J., "mTOR-dependent role of Sestrin2 in regulating tumor progression of human endometrial cancer", Cancers, 12, pp.2015~ (2020)
- Budanov, A. V., "p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling", Cell, 134, pp.451~460 (2008)
- Budanov, A. V., "Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD", Science, 304, pp.596~600 (2004)
- Budanov, A. V., "Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability", Oncogene, 21, pp.6017~6031 (2002)
- Kim, J. S., "Sestrin2 inhibits mTORC1 through modulation of GATOR complexes", Sci. Rep, 5, pp.9502~ (2015)
- Parmigiani, A., "Sestrins inhibit mTORC1 kinase activation through the GATOR complex", Cell Rep, 9, pp.1281~1291 (2014)
- Kim, S. J., "Sestrin2 protects against acetaminophen-induced liver injury", Chem. Biol. Interact, 269, pp.50~58 (2017)
- Dai, J., "Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma", Cancer Med, 7, pp.5691~5703 (2018)
- Ramaesh, K., "Effect of bile acids on fibroblast proliferation and viability", Eye, 12(Pt. 4), pp.717~722 (1998)
- Ljubuncic, P., "Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages", Gut, 39, pp.475~478 (1996)
- Wree, A., "NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice", Hepatology, 59, pp.898~910 (2014)
- Jourdan, T., "Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes", Nat. Med, 19, pp.1132~1140 (2013)
- Kaplowitz, N., "Drug-induced liver injury", Clin. Infect. Dis, 38(Suppl 2), pp.S44~S48 (2004)
- Pasha, M., "Sestrin2 as a novel biomarker and therapeutic target for various diseases", Oxid. Med. Cell. Longev, 2017, pp.3296294~ (2017)
- Bertolotti, A., "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response", Nat. Cell Biol, 2, pp.326~332 (2000)
- Cao, J., "Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK", ATF4, Mol. Cell. Biochem, pp.2012, 364[DOI]
- Marycz, K., "Excessive endoplasmic reticulum stress correlates with impaired mitochondrial dynamics, mitophagy and apoptosis, in liver and adipose tissue, but not in muscles in EMS horses", Int. J. Mol. Sci, 19, pp.165~ (2018)
- Brenner, D. A., "Molecular pathogenesis of liver fibrosis", Trans. Am. Clin. Climatol. Assoc, 120, pp.361~368 (2009)
- Canbay, A., "Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression", Hepatology, 38, pp.1188~1198 (2003)
- Zhan, S. S., "Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo", Hepatology, 43, pp.435~443 (2006)
- Hu, Y. B., "Sestrin 2 attenuates rat hepatic stellate cell(HSC)activation and liver fibrosis via an mTOR", AMPK-dependent mechanism, 2018, pp.51, 2111~2122
- Yang, J. H., "Inhibitory effect of Sestrin 2 on hepatic stellate cell activation and liver fibrosis", Antioxid. Redox Signal, 31, pp.243~259 (2019)
- Gressner, A. M., "Roles of TGF-beta in hepatic fibrosis", Front. Biosci, 7, pp.d793~d807 (2002)
- Benz, C., "Effect of S-adenosylmethionine versus tauroursodeoxycholic acid on bile acid-induced apoptosis and cytolysis in rat hepatocytes", Eur. J. Clin. Invest, 28, pp.577~583 (1998)
- Attili, A. F., "Bile acidinduced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids", Med. Hypotheses, 19, pp.57~69 (1986)
- Sharma, R., "Bile acid toxicity structure-activity relationships : correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line(HET-1A)", Bioorg. Med. Chem, 18, pp.6886~6895 (2010)
- Adachi, T., "The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury", J. Clin. Biochem. Nutr, 54, pp.129~135 (2014)
- Woolbright, B. L., "Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis", Toxicol. Appl. Pharmacol, 283, pp.168~177 (2015)
- Trottier, J., "Profiling circulating and urinary bile acids in patients with biliary obstruction before and after biliary stenting", PLoS ONE, 6, pp.e22094~ (2011)
- Saxton, R. A., "mTOR signaling in growth, metabolism, and disease", Cell, 168, pp.960~976 (2017)
- Yang, F., "Uncoupling of ER", mitochondrial oxidative stress in mTORC1hyperactivation-associated skin hypopigmentation, 2018, pp.138, 669~678
- Liang, Y., "SESN2", sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin(ISO)on human bladder cancers, 2016, pp.12, 1229~1239
- Zhang, X. Y., "Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells", Cell Signal, 25, pp.150~158 (2013)
- Song, S., "Crosstalk of autophagy and apoptosis : Involvement of the dual role of autophagy under ER stress", J. Cell. Physiol, 232, pp.2977~2984 (2017)
- Ogata, M., "Autophagy is activated for cell survival after endoplasmic reticulum stress", Mol. Cell. Biol, 26, pp.9220~9231 (2006)
- Wree, A., "NLRP3 inflammasome activation is required for fibrosis development in NAFLD", J. Mol. Med, 92, pp.1069~1082 (2014)
- Li-xue Wang, "Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells", Cellular and Molecular Life Sciences, 78(24), pp.8209~8227 (2021), Springer Science and Business Media LLC[DOI]
- Ting Ji, "Endoplasmic reticulum stress and NLRP3 inflammasome: Crosstalk in cardiovascular and metabolic disorders", Journal of Cellular Physiology, 234(9), pp.14773~14782 (2019), Wiley[DOI]
- Chen, X., "ER stress activates the NLRP3 inflammasome : a novel mechanism of atherosclerosis", Oxid. Med. Cell. Longev, 2019, pp.3462530~ (2019)