核因子E2相关因子2/血红素加氧酶-1(Nrf2/HO-1)信号通路在酒精性肝病中的作用

马成; 杨慧

doi:10.3969/j.issn.1001-5256.2023.07.028

核因子E2相关因子2/血红素加氧酶-1(Nrf2/HO-1)信号通路在酒精性肝病中的作用

DOI: 10.3969/j.issn.1001-5256.2023.07.028

马成¹,
杨慧^2, , ,

1.
山西医科大学研究生院，太原 030001
2.
山西医科大学第一医院感染病科，太原 030001

基金项目:

山西省省筹资金资助留学人员科研项目 (2020-168)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：马成负责收集文献，撰写论文；杨慧负责拟定写作思路，指导撰写文章，最后定稿及经费支持。

详细信息

通信作者:
杨慧，576371816@qq.com (ORCID：0000-0002-9162-6951)

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出版历程
- 收稿日期: 2022-09-20
- 录用日期: 2022-11-21
- 出版日期: 2023-07-20

Role of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway in alcoholic liver disease

Cheng MA¹,
Hui YANG^{2
, ,
,}

1.
Graduate School of Shanxi Medical University, Taiyuan 030001, China
2.
Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan 030001, China

Research funding:

Scientific Research Project of Shanxi Province Raises Funds to Support Overseas Students (2020-168)

More Information

Corresponding author: YANG Hui, 576371816@qq.com (ORCID: 0000-0002-9162-6951)

摘要

摘要: 酒精性肝病(ALD)在我国的发病率逐年上升，国民的疾病负担日益增加。肝细胞的氧化应激反应是ALD的重要致病机制。核因子E2相关因子2/血红素加氧酶-1(Nrf2/HO-1)信号通路是人体重要的内源性抗氧化应激通路，在氧化应激作用下，Nrf2被激活并发挥其转录活性诱导HO-1高表达。HO-1是体内重要的氧化应激反应蛋白，与其血红素酶解产物(胆红素、CO、铁)共同发挥着抗炎、抗氧化及调控细胞凋亡的作用。本文将对近年来Nrf2/HO-1信号通路在ALD中的研究进展进行综述，力求为ALD的发生发展寻找理论依据及治疗切入点。
- 肝疾病, 酒精性 /
- NF-E2相关因子2 /
- 血红素加氧酶-1 /
- 信号传导
Abstract: The incidence rate of alcoholic liver disease (ALD) is increasing year by year China, and there is a gradual increase in disease burden among Chinese people. Oxidative stress response in hepatocytes is an important pathogenic mechanism of ALD. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway is an important endogenous anti-oxidative stress pathway in the body, and Nrf2 is activated in response to oxidative stress and exerts its transcriptional activity to induce high HO-1 expression. HO-1 is an important oxidative stress response protein and plays a role in anti-inflammation, anti- oxidation, and cell apoptosis regulation together with heme hydrolysis products (bilirubin, carbon monoxide, and iron). This article reviews the research advances in the role of the Nrf2/HO-1 signaling pathway in ALD in recent years, so as to find a theoretical basis for the development and progression of ALD and an entry point for treatment.
- Liver Diseases, Alcoholic /
- NF-E2-Related Factor 2 /
- Heme Oxygenase-1 /
- Signal Transduction

HTML全文

图 1 Nrf2和Keap1分子的结构域

注：a，Nrf2；b，Keap1。

Figure 1. The schematic diagram of Nrf2 and Keap1 domain structure

下载: 全尺寸图片幻灯片

图 2 Nrf2/HO-1信号通路的调控机制

Figure 2. The illustration of regulatory mechanisms for Nrf2/HO-1 signaling pathway

下载: 全尺寸图片幻灯片

参考文献(36)

[1]	Fatty Liver Expert Committee, Chinese Medical Doctor Association, National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association. Guidelines of prevention and treatment for alcoholic liver disease: a 2018 update[J]. J Clin Hepatol, 2018, 34(5): 939-946. DOI: 10.3969/j.issn.1001-5256.2018.05.006. 中国医师协会脂肪性肝病专家委员会, 中华医学会肝病学分会脂肪肝和酒精性肝病学组. 酒精性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34(5): 939-946. DOI: 10.3969/j.issn.1001-5256.2018.05.006.
[2]	SILVA-ISLAS CA, MALDONADO PD. Canonical and non-canonical mechanisms of Nrf2 activation[J]. Pharmacol Res, 2018, 134: 92-99. DOI: 10.1016/j.phrs.2018.06.013.
[3]	SHAW P, CHATTOPADHYAY A. Nrf2-ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms[J]. J Cell Physiol, 2020, 235(4): 3119-3130. DOI: 10.1002/jcp.29219.
[4]	ZHANG A, SUZUKI T, ADACHI S, et al. Distinct regulations of HO-1 gene expression for stress response and substrate induction[J]. Mol Cell Biol, 2021, 41(11): e0023621. DOI: 10.1128/MCB.00236-21.
[5]	RYTER SW. Heme oxygenase-1: An anti-inflammatory effector in cardiovascular, lung, and related metabolic disorders[J]. Antioxidants (Basel), 2022, 11(3): 555. DOI: 10.3390/antiox11030555.
[6]	ZHOU J, ZHENG Q, CHEN Z. The Nrf2 pathway in liver diseases[J]. Front Cell Dev Biol, 2022, 10: 826204. DOI: 10.3389/fcell.2022.826204.
[7]	SHERIFF L, KHAN RS, SABORANO R, et al. Alcoholic hepatitis and metabolic disturbance in female mice: a more tractable model than Nrf2^-/- animals[J]. Dis Model Mech, 2020, 13(12): dmm046383. DOI: 10.1242/dmm.046383.
[8]	WANG G, FU Y, LI J, et al. Aqueous extract of Polygonatum sibiricum ameliorates ethanol-induced mice liver injury via regulation of the Nrf2/ARE pathway[J]. J Food Biochem, 2021, 45(1): e13537. DOI: 10.1111/jfbc.13537.
[9]	WANG X, CHANG X, ZHAN H, et al. Curcumin and Baicalin ameliorate ethanol-induced liver oxidative damage via the Nrf2/HO-1 pathway[J]. J Food Biochem, 2020. DOI: 10.1111/jfbc.13425.[Online ahead of print]
[10]	FERDOUSE A, CLUGSTON RD. Pathogenesis of alcohol-associated fatty liver: lessons from transgenic mice[J]. Front Physiol, 2022, 13: 940974. DOI: 10.3389/fphys.2022.940974.
[11]	OSNA NA, DONOHUE TM Jr, KHARBANDA KK. Alcoholic liver disease: pathogenesis and current management[J]. Alcohol Res, 2017, 38(2): 147-161.
[12]	SEEN S. Chronic liver disease and oxidative stress - a narrative review[J]. Expert Rev Gastroenterol Hepatol, 2021, 15(9): 1021-1035. DOI: 10.1080/17474124.2021.1949289.
[13]	CHEN WY, SHU FM, WANG H, et al. Role of the cytochrome P450 family in metabolic-associated liver diseases[J]. J Chin Hepatol, 2022, 38(9): 2182-2187. DOI: 10.3969/j.issn.1001-5256.2022.09.045. 陈玮钰, 舒发明, 王涵, 等. 细胞色素P450家族在肝脏代谢相关疾病中的作用[J]. 临床肝胆病杂志, 2022, 38(9): 2182-2187. DOI: 10.3969/j.issn.1001-5256.2022.09.045.
[14]	WU KC, LIU J, KLAASSEN CD. Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation[J]. Toxicol Appl Pharmacol, 2012, 262(3): 321-329. DOI: 10.1016/j.taap.2012.05.010.
[15]	PALIPOCH S, KOOMHIN P, PUNSAWAD C, et al. Heme oxygenase-1 alleviates alcoholic liver steatosis: histopathological study[J]. J Toxicol Pathol, 2016, 29(1): 7-15. DOI: 10.1293/tox.2015-0035.
[16]	BUKO V, ZAVODNIK I, BUDRYN G, et al. Chlorogenic acid protects against advanced alcoholic steatohepatitis in rats via modulation of redox homeostasis, inflammation, and lipogenesis[J]. Nutrients, 2021, 13(11). DOI: 10.3390/nu13114155.
[17]	TOROK NJ. Update on alcoholic hepatitis[J]. Biomolecules, 2015, 5(4): 2978-2986. DOI: 10.3390/biom5042978.
[18]	HOSSEINI N, SHOR J, SZABO G. Alcoholic hepatitis: a review[J]. Alcohol Alcohol, 2019, 54(4): 408-416. DOI: 10.1093/alcalc/agz036.
[19]	RAMOS-TOVAR E, MURIEL P. Free radicals, antioxidants, nuclear factor-E2-related factor-2 and liver damage[J]. J Appl Toxicol, 2020, 40(1): 151-168. DOI: 10.1002/jat.3880.
[20]	GALICIA-MORENO M, LUCANO-LANDEROS S, MONROY-RAMIREZ HC, et al. Roles of Nrf2 in liver diseases: molecular, pharmacological, and epigenetic aspects[J]. Antioxidants (Basel), 2020, 9(10): 980. DOI: 10.3390/antiox9100980.
[21]	HONG DG, SONG GY, EOM CB, et al. Loss of ERdj5 exacerbates oxidative stress in mice with alcoholic liver disease via suppressing Nrf2[J]. Free Radic Biol Med, 2022, 184: 42-52. DOI: 10.1016/j.freeradbiomed.2022.03.027.
[22]	RYTER SW. Heme oxgenase-1, a cardinal modulator of regulated cell death and inflammation[J]. Cells, 2021, 10(3): 515. DOI: 10.3390/cells10030515.
[23]	LIU S, TIAN L, CHAI G, et al. Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation[J]. Food Funct, 2018, 9(8): 4184-4193. DOI: 10.1039/c8fo00650d.
[24]	ZHANG Y, WU Y, SHEN W, et al. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review)[J]. Mol Med Rep, 2022, 25(6): 208. DOI: 10.3892/mmr.2022.12724.
[25]	LI T, LIU HB, HU WY, et al. Role of inflammation in hepatic fibrosis[J]. J Clin Hepatol, 2022, 38(10): 2368-2372. DOI: 10.3969/j.issn.1001-5256.2022.10.032. 李婷, 刘华宝, 胡文艳, 等. 炎症在肝纤维化中的作用[J]. 临床肝胆病杂志, 2022, 38(10): 2368-2372. DOI: 10.3969/j.issn.1001-5256.2022.10.032.
[26]	CHENG ML, LU YF, CHEN H, et al. Liver expression of Nrf2-related genes in different liver diseases[J]. Hepatobiliary Pancreat Dis Int, 2015, 14(5): 485-491. DOI: 10.1016/s1499-3872(15)60425-8.
[27]	NUNES DOS SANTOS K, FLORENTINO RM, FRANÇA A, et al. Polymorphism in the promoter region of NFE2L2 gene is a genetic marker of susceptibility to cirrhosis associated with alcohol abuse[J]. Int J Mol Sci, 2019, 20(14): 3589. DOI: 10.3390/ijms20143589.
[28]	NI YH, HUO LJ, LI TT. Antioxidant axis Nrf2-keap1-ARE in inhibition of alcoholic liver fibrosis by IL-22[J]. World J Gastroenterol, 2017, 23(11): 2002-2011. DOI: 10.3748/wjg.v23.i11.2002.
[29]	LIU Y, KUANG Q, DAI X, et al. Deficiency in inactive rhomboid protein2 (iRhom2) alleviates alcoholic liver fibrosis by suppressing inflammation and oxidative stress[J]. Int J Mol Sci, 2022, 23(14): 7701. DOI: 10.3390/ijms23147701.
[30]	YANG H, ZHANG L, CHEN J, et al. Heme oxygenase-1 inhibits the proliferation of hepatic stellate cells by activating PPARγ and suppressing NF-κB[J]. Comput Math Methods Med, 2022, 2022: 8920861. DOI: 10.1155/2022/8920861.
[31]	BUCHANAN R, SINCLAIR J. Alcohol use disorder and the liver[J]. Addiction, 2021, 116(5): 1270-1278. DOI: 10.1111/add.15204.
[32]	GANNE-CARRIÉ N, NAHON P. Hepatocellular carcinoma in the setting of alcohol-related liver disease[J]. J Hepatol, 2019, 70(2): 284-293. DOI: 10.1016/j.jhep.2018.10.008.
[33]	ZHANG C, LI L, HOU S, et al. Astragaloside Ⅳ inhibits hepatocellular carcinoma by continually suppressing the development of fibrosis and regulating pSmad3C/3L and Nrf2/HO-1 pathways[J]. J Ethnopharmacol, 2021, 279: 114350. DOI: 10.1016/j.jep.2021.114350.
[34]	ZOU C, ZOU C, CHENG W, et al. Heme oxygenase-1 retards hepatocellular carcinoma progression through the microRNA pathway[J]. Oncol Rep, 2016, 36(5): 2715-2722. DOI: 10.3892/or.2016.5056.
[35]	RAGHUNATH A, SUNDARRAJ K, ARFUSO F, et al. Dysregulation of Nrf2 in hepatocellular carcinoma: role in cancer progression and chemoresistance[J]. Cancers (Basel), 2018, 10(12): 481. DOI: 10.3390/cancers10120481.
[36]	WU MM, HSIEH FI, HSU LI, et al. GT-repeat polymorphism in the HO-1 gene promoter Is associated with risk of liver cancer: a follow-up study from arseniasis-endemic areas in Taiwan[J]. J Clin Med, 2021, 10(7): 1489. DOI: 10.3390/jcm10071489.