[1]吕枭锐,朱惠娟,龚凤英.P62-Nrf2通路在非酒精性脂肪性肝炎中的作用[J].国际内分泌代谢杂志,2020,40(06):395-398.[doi:10.3760/cma.j.cn121383-20200404-04010]
 LV Xiaorui,Zhu Huijuan,Gong Fengying.Role of P62-Nrf2 pathway in nonalcoholic steatohepatitis[J].International Journal of Endocrinology and Metabolism,2020,40(06):395-398.[doi:10.3760/cma.j.cn121383-20200404-04010]
点击复制

P62-Nrf2通路在非酒精性脂肪性肝炎中的作用()
分享到:

《国际内分泌代谢杂志》[ISSN:1673-4157/CN:12-1383/R]

卷:
40
期数:
2020年06期
页码:
395-398
栏目:
综述
出版日期:
2020-11-20

文章信息/Info

Title:
Role of P62-Nrf2 pathway in nonalcoholic steatohepatitis
作者:
吕枭锐朱惠娟龚凤英
中国医学科学院,北京协和医学院,北京协和医院内分泌科,卫生健康委内分泌重点实验室,协和转化医学中心 100730
Author(s):
LV Xiaorui Zhu Huijuan Gong Fengying
Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, The Translational Medicine Center of PUMCH, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
关键词:
核因子E2相关因子2 P62 非酒精性脂肪性肝炎 氧化应激
Keywords:
Nuclear factor E2-related factor 2 P62 Nonalcoholic steatohepatitis Oxidative stress
DOI:
10.3760/cma.j.cn121383-20200404-04010
文献标志码:
A
摘要:
非酒精性脂肪性肝病(NAFLD)是目前最常见的慢性肝病,大约有1/3的NAFLD患者会发展为非酒精性脂肪性肝炎(NASH)。多数学者认为,NASH的发病主要与肝脏脂肪异常积累和氧化应激等因素有关。核因子E2相关因子2(Nrf2)是细胞内抗氧化应激反应中的关键因子,而P62是一种多功能蛋白质,能够通过多种途径激活Nrf2。研究发现,抑制P62-Nrf2通路会加重肝脏脂肪变性、炎性反应和纤维化程度。而一些应用于其他疾病的药物,包括氯硝柳胺乙醇胺、依西替米等能够通过激活该通路抑制NASH的发生、发展。
Abstract:
Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease currently, and about one-third of which will develop nonalcoholic steatohepatitis(NASH). Most scholars believe that the pathogenesis of NASH is mainly related to the abnormal accumulation of liver fat and oxidative stress. Nuclear factor E2-related factor 2(Nrf2)is a key factor in intracellular antioxidant stress response, and P62 is a multifunctional protein, which can activate Nrf2 through many ways. It is found that inhibition of P62-Nrf2 pathway could aggravate steatosis, inflammatory response and fibrosis of liver. It has been reported that some drugs used in other diseases, including niclosamide ethanolamine and ezetimibe, can inhibit the development of NASH by activating this pathway.

参考文献/References:

[1] Dietrich P,Hellerbrand C. Non-alcoholic fatty liver disease,obesity and the metabolic syndrome[J].Best Pract Res Clin Gastroenterol,2014,28(4):637-653.DOI:10.1016/j.bpg.2014.07.008.
[2] Kawano Y,Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease[J].J Gastroenterol,2013,48(4):434-441.DOI:10.1007/s00535-013-0758-5.
[3] Begriche K, Igoudjil A, Pessayre D, et al. Mitochondrial dysfunction in NASH:causes, consequences and possible means to prevent it[J].Mitochondrion, 2006,6(1):DOI:1-28.10.1016/j.mito.2005.10.004.
[4] LiS,Tan HY,Wang N, et al. The role of oxidative stress and antioxidants in liver diseases[J].Int J Mol Sci, 2015,16(11): 26087-26124.DOI:10.3390/ijms161125942.
[5] Komatsu M, Kageyama S, Ichimura Y. P62/SQSTM1/A170:physiology and pathology[J].Pharmacol Res,2012,66(6):457-462.10.DOI:1016/j.phrs.2012.07.004.
[6] Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway[J].Annu Rev Pharmacol Toxicol,2007,47(1):89-116.DOI:10.1146/annurev.pharmtox.46.120604.141046.
[7] Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress[J].Mol Cell Biol, 2003,23(22):8137-8151.DOI:10.1128/mcb.23.22.8137-8151.2003.
[8] Wang X, Hai CX. ROS acts as a double-edged sword in the pathogenesis of type 2 diabetes mellitus:is Nrf2 a potential target for the treatment?[J].Mini Rev Med Chem, 2011, 11(12):1082-1092.DOI:10.2174/138955711797247761.
[9] Lau A, Wang XJ, Zhao F, et al. A noncanonical mechanism of Nrf2 activation by autophagy deficiency:direct interaction between Keap1 and P62[J].Mol Cell Biol,2010,30(13):3275-3285.DOI:10.1128/MCB.00248-10.
[10] Taguchi K, Fujikawa N, Komatsu M, et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis[J].Proc Natl Acad Sci,2012,109(34):13561-13566.DOI:10.1073/pnas.1121572109.
[11] Jain A, Lamark T, Sjottem E, et al. P62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription[J].J Biol Chem, 2010,285(29):22576-22591.DOI:10.1074/jbc.M110.118976.
[12] Wang C, Cui Y, Li C, et al. Nrf2 deletion causes "benign" simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet[J].Lipids Health Dis,2013,12(1):165.DOI:10.1186/1476-511X-12-165.
[13] Meakin PJ, Chowdhry S, Sharma RS, et al. Susceptibility of Nrf2-Null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance[J].Mol Cell Biol,2014,34(17): 3305-3320.DOI:10.1128/MCB.00677-14.
[14] Lee LY, Kohler UA, Zhang L, et al. Activation of the Nrf2-ARE pathway in hepatocytes protects against steatosis in nutritionally induced non-alcoholic steatohepatitis in mice[J].Toxicol Sci,2014,142(2):361-374.DOI:10.1093/toxsci/kfu184.
[15] Chowdhry S, Nazmy MH, Meakin PJ, et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis[J].Free Radic Biol Med,2010,48(2):357-371.DOI:10.1016/j.freeradbiomed.2009.11.007.
[16] Pierluigi R, Hannah D, Stephanie E, et al. Genetic Nrf2 overactivation inhibits the deleterious effects induced by hepatocyte-specific c-met deletion during the progression of NASH[J].Oxid Med Cell Longev,2017,2017:1-15.DOI:10.1155/2017/3420286.
[17] Komatsu M,Kurokawa H,Waguri S,et al.The selective autophagy substrate P62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1[J].Nat Cell Biol, 2010,12:399-403.DOI:10.1038/ncb2021
[18] Akiyama K, Warabi E, Okada K, et al. Deletion of both P62 and Nrf2 spontaneously results in the development of nonalcoholic steatohepatitis[J]. Exp Anim, 2018,67(2):201-218.DOI:10.1538/expanim.17-0112.
[19] Park JS, Dong HK, Da HL, et al. Concerted action of P62 and Nrf2 protects cells from palmitic acid-induced lipotoxicity[J].Biochem Biophys Res Commun,2015,466(1):131-137.DOI:10.1016/j.bbrc.2015.08.120.
[20] Lee DH, Park JS, Lee YS, et al. SQSTM1/P62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity[J].Autophagy, 2020,10: 1-25.DOI:10.1080/15548627.2020.1712108.
[21] Tao H, Zhang Y, Zeng X, et al. Niclosamide ethanolamine improves blood glycemic control and reduces hepatic steatosis in mice[J].Nat Med,2014, 20(11):1263-1269.DOI: 10.1038/nm.3699.
[22] Park JS,Lee YS,Lee DH,et al. Repositioning of niclosamide ethanolamine(NEN), an anthelmintic drug, for the treatment of lipotoxicity[J].Free Radic Biol Med,2019,137:143-157.DOI:10.1016/j.freeradbiomed.2019.04.030.
[23] Park H,Shima T,Yamaguchi K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease[J].J Gastroenterol,2011,46(1):101-107.DOI:10.1007/s00535-010-0291-8.
[24] Nozaki Y,Fujita K,Yoneda M, et al. Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease[J].J Hepatol,2009,51(3):548-556.DOI:10.1016/j.jhep.2009.05.017.
[25] Lee DH,Han DH,Nam KT, et al. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis[J].Free Radic Biol Med,2016,99:520-532.DOI:10.1016/j.freeradbiomed.2016.09.009.

备注/Memo

备注/Memo:
基金项目:北京市自然科学基金(7182130,7082079); 国家自然科学基金(81370898,30771026,30540036); 人社部留学人员科技活动项目择优资助经费(启动类); 国家临床重点专科建设项目单位(WBYZ2011-873) 通信作者:龚凤英,Email:fygong@sina.com
更新日期/Last Update: 2020-11-20