CCAAT/Enhancer-binding Protein Homologous Protein Promotes ROS-mediated Liver Ischemia and Reperfusion Injury by Inhibiting Mitophagy in Hepatocytes.
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
01 01 2023
01 01 2023
Historique:
pubmed:
14
7
2022
medline:
15
12
2022
entrez:
13
7
2022
Statut:
ppublish
Résumé
Liver ischemia and reperfusion (IR) injury represent a major risk factor in both partial hepatectomy and liver transplantation. CCAAT/enhancer-binding protein homologous protein (CHOP) is a key regulator of cell death, its precise molecular basis in regulating hepatocyte death during liver IR has not been delineated. Hepatocellular CHOP deficient mice were generated by bone marrow chimera models using global CHOP knockout mice. Liver partial warm ischemia model and hypoxia/reoxygenation model of primary hepatocytes were applied. Liver injury and mitophagy-related signaling pathways were investigated. IR-stressed patient liver tissues and serum samples were analyzed as well. Mice with hepatocellular CHOP deficiency exhibited alleviated cell death, decreased reactive oxygen species (ROS) expression, and enhanced mitophagy in hepatocytes after IR, confirmed by in vitro studies of hepatocytes after hypoxia/reoxygenation. Mitochondria ROS scavenge by Mito TEMPO effectively attenuated hepatocyte death and liver IR injury of wild-type mice, whereas no significant effects were observed in hepatocellular CHOP -deficient mice. CHOP depletion upregulated dynamin-related protein 1 and Beclin-1 activation in the mitochondria of hepatocytes leading to enhanced mitophagy. Following IR, increased CHOP expression and impaired mitophagy activation were observed in the livers of patients undergoing hepatectomy. N-acetyl cysteine pretreatment significantly improved the liver function of patients after surgery. IR-induced CHOP activation exacerbates ROS-mediated hepatocyte death by inhibiting dynamin-related protein 1-Beclin-1-dependent mitophagy.
Sections du résumé
BACKGROUND
Liver ischemia and reperfusion (IR) injury represent a major risk factor in both partial hepatectomy and liver transplantation. CCAAT/enhancer-binding protein homologous protein (CHOP) is a key regulator of cell death, its precise molecular basis in regulating hepatocyte death during liver IR has not been delineated.
METHODS
Hepatocellular CHOP deficient mice were generated by bone marrow chimera models using global CHOP knockout mice. Liver partial warm ischemia model and hypoxia/reoxygenation model of primary hepatocytes were applied. Liver injury and mitophagy-related signaling pathways were investigated. IR-stressed patient liver tissues and serum samples were analyzed as well.
RESULTS
Mice with hepatocellular CHOP deficiency exhibited alleviated cell death, decreased reactive oxygen species (ROS) expression, and enhanced mitophagy in hepatocytes after IR, confirmed by in vitro studies of hepatocytes after hypoxia/reoxygenation. Mitochondria ROS scavenge by Mito TEMPO effectively attenuated hepatocyte death and liver IR injury of wild-type mice, whereas no significant effects were observed in hepatocellular CHOP -deficient mice. CHOP depletion upregulated dynamin-related protein 1 and Beclin-1 activation in the mitochondria of hepatocytes leading to enhanced mitophagy. Following IR, increased CHOP expression and impaired mitophagy activation were observed in the livers of patients undergoing hepatectomy. N-acetyl cysteine pretreatment significantly improved the liver function of patients after surgery.
CONCLUSIONS
IR-induced CHOP activation exacerbates ROS-mediated hepatocyte death by inhibiting dynamin-related protein 1-Beclin-1-dependent mitophagy.
Identifiants
pubmed: 35821597
doi: 10.1097/TP.0000000000004244
pii: 00007890-202301000-00018
pmc: PMC9746334
doi:
Substances chimiques
Beclin-1
0
Ddit3 protein, mouse
0
Transcription Factor CHOP
147336-12-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129-139Informations de copyright
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
Références
Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol Cell. 2018;69:169–181.
Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7:1013–1030.
Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54:795–809.
Zhang C, Huang J, An W. Hepatic stimulator substance resists hepatic ischemia/reperfusion injury by regulating Drp1 translocation and activation. Hepatology (Baltimore, MD). 2017;66:1989–2001.
Uzi D, Barda L, Scaiewicz V, et al. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol. 2013;59:495–503.
Lebeaupin C, Proics E, de Bieville CH, et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis. 2015;6:e1879.
McCullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21:1249–1259.
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89–102.
Rinella ME, Siddiqui MS, Gardikiotes K, et al. Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis. Hepatology (Baltimore, MD). 2011;54:1600–1609.
Inaba Y, Furutani T, Kimura K, et al. Growth arrest and DNA damage-inducible 34 regulates liver regeneration in hepatic steatosis in mice. Hepatology (Baltimore, MD). 2015;61:1343–1356.
Liu R, Li X, Huang Z, et al. C/EBP homologous protein-induced loss of intestinal epithelial stemness contributes to bile duct ligation-induced cholestatic liver injury in mice. Hepatology (Baltimore, Md). 2018;67:1441–1457.
Cybulsky AV. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat Rev Nephrol. 2017;13:681–696.
Senft D, Ronai ZA. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci. 2015;40:141–148.
Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6:463–477.
Vera-Ramirez L, Vodnala SK, Nini R, et al. Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence. Nat Commun. 2018;9:1944.
Zhou H, Zhu J, Yue S, et al. The dichotomy of endoplasmic reticulum stress response in liver ischemia-reperfusion injury. Transplantation. 2016;100:365–372.
Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science (New York, NY). 2019;366:818–822.
Zhong W, Rao Z, Rao J, et al. Aging aggravated liver ischemia and reperfusion injury by promoting STING-mediated NLRP3 activation in macrophages. Aging Cell. 2020;19:e13186.
Zheng J, Chen L, Lu T, et al. MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation. Cell Death Dis. 2020;11:256.
Wada S, Hatano E, Yoh T, et al. CAAT/enhancer binding protein-homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice. Liver Transpl. 2018;24:645–654.
Marin V, Poulsen K, Odena G, et al. Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients. J Hepatol. 2017;67:1018–1025.
Lu L, Yue S, Jiang L, et al. Myeloid Notch1 deficiency activates the RhoA/ROCK pathway and aggravates hepatocellular damage in mouse ischemic livers. Hepatology (Baltimore, MD). 2018;67:1041–1055.
Gramignoli R, Green ML, Tahan V, et al. Development and application of purified tissue dissociation enzyme mixtures for human hepatocyte isolation. Cell Transplant. 2012;21:1245–1260.
Ni HM, Du K, You M, et al. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol. 2013;183:1815–1825.
Wang X, Mao W, Fang C, et al. Dusp14 protects against hepatic ischaemia-reperfusion injury via Tak1 suppression. J Hepatol. 2017. S0168-8278(17)32275-4. doi:10.1016/j.jhep.2017.08.032
doi: 10.1016/j.jhep.2017.08.032
Elias-Miró M, Jiménez-Castro MB, Rodés J, et al. Current knowledge on oxidative stress in hepatic ischemia/reperfusion. Free Radic Res. 2013;47:555–568.
Lesnefsky EJ, Chen Q, Tandler B, et al. Mitochondrial dysfunction and myocardial ischemia-reperfusion: implications for novel therapies. Annu Rev Pharmacol Toxicol. 2017;57:535–565.
Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812–1824.
Kerr JS, Adriaanse BA, Greig NH, et al. Mitophagy and Alzheimer's disease: cellular and molecular mechanisms. Trends Neurosci. 2017;40:151–166.
Xie JH, Li YY, Jin J. The essential functions of mitochondrial dynamics in immune cells. Cell Mol Immunol. 2020;17:712–721.
Yamada T, Murata D, Adachi Y, et al. Mitochondrial stasis reveals p62-mediated ubiquitination in parkin-independent mitophagy and mitigates nonalcoholic fatty liver disease. Cell Metab. 2018;28:588–604.e5.
Yue S, Zhou H, Wang X, et al. Prolonged ischemia triggers necrotic depletion of tissue-resident macrophages to facilitate inflammatory immune activation in liver ischemia reperfusion injury. J Immunol. 2017;198:3588–3595.
Ferlito M, Wang Q, Fulton WB, et al. Hydrogen sulfide [corrected] increases survival during sepsis: protective effect of CHOP inhibition. J Immunol. 2014;192:1806–1814.
Malhi H, Kropp EM, Clavo VF, et al. C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. J Biol Chem. 2013;288:18624–18642.
Soon RK Jr, Yan JS, Grenert JP, et al. Stress signaling in the methionine-choline-deficient model of murine fatty liver disease. Gastroenterology. 2010;139:1730–1739, 1739.e1.
Toriguchi K, Hatano E, Tanabe K, et al. Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency. J Gastroenterol Hepatol. 2014;29:1109–1118.
Rao Z, Sun J, Pan X, et al. Hyperglycemia aggravates hepatic ischemia and reperfusion injury by inhibiting liver-resident macrophage M2 polarization via C/EBP homologous protein-mediated endoplasmic reticulum stress. Front Immunol. 2017;8:1299.
Yamada T, Dawson TM, Yanagawa T, et al. SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. Autophagy. 2019;15:2012–2018.
Ikeda Y, Shirakabe A, Maejima Y, et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. 2015;116:264–278.
Saito T, Nah J, Oka SI, et al. An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. J Clin Invest. 2019;129:802–819.
Ong SB, Subrayan S, Lim SY, et al. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation. 2010;121:2012–2022.
Flippo KH, Gnanasekaran A, Perkins GA, et al. AKAP1 protects from cerebral ischemic stroke by inhibiting Drp1-dependent mitochondrial fission. J Neurosci. 2018;38:8233–8242.
Flippo KH, Lin Z, Dickey AS, et al. Deletion of a neuronal Drp1 activator protects against cerebral ischemia. J Neurosci. 2020;40:3119–3129.
Zuo W, Yang PF, Chen J, et al. Drp-1, a potential therapeutic target for brain ischaemic stroke. Br J Pharmacol. 2016;173:1665–1677.
Fan P, Yu XY, Xie XH, et al. Mitophagy is a protective response against oxidative damage in bone marrow mesenchymal stem cells. Life Sci. 2019;229:36–45.
Friedman JR, Lackner LL, West M, et al. ER tubules mark sites of mitochondrial division. Science (New York, NY). 2011;334:358–362.
Hamasaki M, Furuta N, Matsuda A, et al. Autophagosomes form at ER-mitochondria contact sites. Nature. 2013;495:389–393.
Choubey V, Cagalinec M, Liiv J, et al. BECN1 is involved in the initiation of mitophagy: it facilitates PARK2 translocation to mitochondria. Autophagy. 2014;10:1105–1119.
Cheng B, Xu A, Qiao M, et al. BECN1s, a short splice variant of BECN1, functions in mitophagy. Autophagy. 2015;11:2048–2056.
Shirakabe A, Zhai P, Ikeda Y, et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation. 2016;133:1249–1263.
Kumar M, Shelly A, Dahiya P, et al. Aeromonas hydrophila inhibits autophagy triggering cytosolic translocation of mtDNA which activates the pro-apoptotic caspase-1/IL-1β-nitric oxide axis in headkidney macrophages. Virulence. 2022;13:60–76.
Chen Y, Park HJ, Park J, et al. Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression. Faseb J. 2019;33:13905–13919.
Zeeshan HM, Lee GH, Kim HR, et al. Endoplasmic reticulum stress and associated ROS. Int J Mol Sci. 2016;17:327.
Manuel AM, Walla MD, Dorn MT, et al. Fumarate and oxidative stress synergize to promote stability of C/EBP homologous protein in the adipocyte. Free Radic Biol Med. 2020;148:70–82.
Zhu Q, Liu Z, Wang Y, et al. Endoplasmic reticulum stress manipulates autophagic response that antagonizes polybrominated diphenyl ethers quinone induced cytotoxicity in microglial BV2 cells. J Hazard Mater. 2021;411:124958.
Paridaens A, Raevens S, Colle I, et al. Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication. Liver Int. 2017;37:748–756.