Nrf2信号通路与肝细胞凋亡研究进展

doi:10.3969/j.issn.1672-5069.2016.03.031

摘要/Abstract

摘要： 肝细胞凋亡可分为生理性和病理性两种。当肝细胞凋亡受到抑制或是凋亡过度时，都会导致疾病的发生。活性氧是诱导细胞内源性凋亡的因素之一。研究显示，转录因NF-E2相关因子2（Nrf2）在机体抗氧化、抗炎、抗肿瘤等方面都起到了重要的作用。本文重点介绍了Nrf2的相关通路及其在肝细胞受到氧化应激时发挥抗凋亡作用的研究进展。

关键词: 肝细胞, 凋亡, 活性氧, 转录因NF-E2相关因子2

Abstract: Hepatocyte apoptosis can be divided into physiological and pathologicalapoptosis. Both of them are relevant to the progression of liver disease. Reactive oxygen species（ROS） play an important role in the induction of hepatocyteapoptosis. Recently， some reports show thatnuclear factor E2-related fator 2（Nrf-2） represents one of the mostimportant cellular defense mechanisms against oxidative stress，inflammatory and tumorigenesis. Here，we reviewed the mechanisms of signal transduction involved in Nrf-2 related pathway and its possible roles in the process of hepatic apoptosis under oxidative stress.

Key words: Hepatocytes, Apoptosis, Reactive oxygen species, Nuclear factor E2-related fator 2

崔丹，杨宝山. Nrf2信号通路与肝细胞凋亡研究进展[J]. 实用肝脏病杂志, 2016, 19(3): 365-368.

Cui Dan,Yang Baoshan. Role of Nrf2 in the regulation of hepatocyte apoptosis[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2016, 19(3): 365-368.

参考文献

[1] Chan K，Lu R，Chang JC，et al. NRF2，a member of the NFE2 family of transcription factors，is not essential for murine erythropoiesis，growth，and development. Proc Natl Acad Sci U S A，1996，93（24）:13943-13948.
[2] Wakabayashi N，Shin S，Slocum SL，et al. Regulation of notch1 signaling by nrf2:implications for tissue regeneration. Sci Signal，2010，3（130）:ra52.
[3] Buitrago-Molina LE，Marhenke S，Longerich T，et al. The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice. Hepatology，2013，58（3）:1143-1152.
[4] Pedrosa AM，Faine LA，Grosso DM，et al. Electronegative LDL induction of apoptosis in macrophages:involvement of Nrf2. Biochim Biophys Acta，2010，1801（4）:430-437.
[5] Spierings D，McStay G，Saleh M，et al. Connected to death: the （unexpurgated） mitochondrial pathway of apoptosis. Science， 2005，310（5745）:66-67.
[6] Boyce M，Yuan J. Cellular response to endoplasmic reticulum stress:a matter of life or death. Cell Death Differ，2006，13（3）:363-373.
[7] Rolo AP，Teodoro JS，Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med，2012，52（1）:59-69.
[8] Aldaba-Muruato LR，Moreno MG，Shibayama M，et al. Protective effects of allopurinol against acute liver damage and cirrhosis induced by carbon tetrachloride:modulation of NF-κB， cytokine production and oxidative stress. Biochim Biophys Acta， 2012，1820（2）:65-75.
[9] Ivanov AV，Smirnova OA，Ivanova ON，et al. Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS One，2011，6（9）:e24957.
[10] 杨联军，朱立新，董为人，等. 氧化应激诱导髓核细胞凋亡中细胞内活性氧及线粒体膜电位的变化. 实用医学杂志，2014，30（2）:193-195.
[11] Sharma V，Anderson D，Dhawan A. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human liver cells（HepG2）. Apoptosis， 2012，17（8）:852-870.
[12] Chandel NS，McClintock DS，Feliciano CE，et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia:a mechanism of O2 sensing. J Biol Chem，2000，275（33）:25130-25138.
[13] Allen RG，Balin AK. Oxidative influence on development and differentiation:an overview of a free radical theory of development. Free Radic Biol Med，1989，6（6）:631-661.
[14] Bosoi CR，Rose CF. Oxidative stress:a systemic factor implicated in the pathogenesis of hepatic encephalopathy. Metab Brain Dis，2013，28（2）:175-178.
[15] Itoh K，Wakabayashi N，Katoh Y，et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev， 1999，13（1）:76-86.
[16] Katsuoka F，Motohashi H，Ishii T，et al. Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol，2005，25（18）:8044-8051.
[17] Tong KI，Katoh Y，Kusunoki H，et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs:characterization of the two-site molecular recognition model. Mol Cell Biol，2006，26（8）:2887-2900.
[18] Nioi P，Nguyen T，Sherratt PJ，et al. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol，2005，25（24）:10895-10906.
[19] Sato K，Yama K，Murao Y，et al. Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation. Redox Biol，2013，2:15-21.
[20] McMahon M，Thomas N，Itoh K，et al. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains，the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J Biol Chem，2004，279（30）:31556-31567.
[21] Ferlay J，Shin HR，Bray F，et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008. Int J Cancer，2010，127（12）:2893-2917.
[22] Liu Z，Xiang Y，Sun G. The KCTD family of proteins: structure，function，disease relevance. Cell Biosci，2013，3（1）:45.
[23] Sekhar KR，Rachakonda G，Freeman ML. Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol Appl Pharmacol，2010，244（1）:21-26.
[24] Holland R，Fishbein JC. Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1. Antioxid Redox Signal， 2010，13（11）:1749-1761.
[25] Hayes JD，McMahon M，Chowdhry S，et al. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal，2010，13（11）:1713-1748.
[26] Itoh K， Wakabayashi N，Katoh Y，et al. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells，2003，8（4）:379-391.
[27] Klaassen CD，Reisman SA. Nrf2 the rescue:effects of the antioxidative/electrophilic response on the liver. Toxicol Appl Pharmacol，2010，244（1）:57-65.
[28] Maher J，Yamamoto M. The rise of antioxidant signaling--the evolution and hormetic actions of Nrf2. Toxicol Appl Pharmacol，2010，244（1）:4-15.
[29] Li Y，Paonessa JD，Zhang Y. Mechanism of chemical activation of Nrf2. PLoS One，2012，7（4）:e35122.
[30] Zou Y，Lee J，Nambiar SM，et al. Nrf2 is involved in maintaining hepatocyte identity during liver regeneration. PLoS One，2014，9（9）:e107423.
[31] Ron D，Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol，2007，8（7）:519-529.
[32] Xie W，Pariollaud M，Wixted WE，et al. Identification and characterization of PERK activators by phenotypic screening and their effects on NRF2 activation. PLoS One，2015，10（3）:e0119738.
[33] Tao TQ，Wang XR，Liu M，et al. Myofibrillogenesis regulator-1 attenuated hypoxia/reoxygenation-induced apoptosis by inhibiting the PERK/Nrf2 pathway in neonatal rat cardiomyocytes. Apoptosis，2015，20（3）:285-297.
[34] Chia AJ，Goldring CE，Kitteringham NR，et al. Differential effect of covalent protein modification and glutathione depletion on the transcriptional response of Nrf2 and NF-kappaB. Biochem Pharmacol，2010，80（3）:410-421.
[35] Khodagholi F，Tusi SK. Stabilization of Nrf2 by tBHQ prevents LPS-induced apoptosis in differentiated PC12 cells. Mol Cell Biochem，2011，354（1-2）:97-112.
[36] 曹旭，肖海兵，杨燕，等. Nrf2活化剂SFP对MPP+所致PC12细胞氧化应激损伤的保护作用. 华中科技大学学报（医学版）， 2013，42（2）:143-147.
[37] 廖嘉仪，熊天琴，康萨?索朗其美，等. 甲嘎松汤调控Nrf2，Bach1表达保护氧化应激肝细胞. 中国实验方剂学杂志，2015，21（3）:118-124.
[38] 庞纯，蒋萍，季莉莉. 黄芩素激活核转录因子Nrf2拮抗肝毒性的研究. 中国药理学通报，2014，30（4）:546-549.
[39] 李强，赵曙光，王旭霞，等. 姜黄素激活转录因子Nrf2对人肝细胞氧化应激的影响. 胃肠病学和肝病学杂志，2010，19（2）:154-156.
[40] Leong PK，Chiu PY，Chen N，et al. Schisandrin B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 hepatocytes. Free Radic Res，2011，45（4）:483-495.
[41] Nguyen T，Sherratt PJ，Huang HC，et al. Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem， 2003，278（7）:4536-4541.
[42] Cho JM，Manandhar S，Lee HR，et al. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett，2008，260（1-2）:96-108.