铁死亡在非酒精性脂肪性肝病发病和治疗中的作用

吴龙云; 鲁晓岚

doi:10.3969/j.issn.1001-5256.2023.07.025

铁死亡在非酒精性脂肪性肝病发病和治疗中的作用

DOI: 10.3969/j.issn.1001-5256.2023.07.025

吴龙云,
鲁晓岚^, ,

上海市浦东医院(复旦大学附属浦东医院)消化内科，上海 201399

基金项目:

国家自然科学基金 (82070587)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：吴龙云负责论文构思，文献检索及分析，表格制作，论文撰写；鲁晓岚负责论文构思，文章润色及修订。

详细信息

通信作者:
鲁晓岚，xiaolan_lu@163.com (ORCID：0000-0001-5745-6373)

计量
- 文章访问数: 584
- HTML全文浏览量: 279
- PDF下载量: 75
- 被引次数: 0
出版历程
- 收稿日期: 2022-10-14
- 录用日期: 2022-12-12
- 出版日期: 2023-07-20

Research advances in ferroptosis in the pathogenesis and treatment of nonalcoholic fatty liver disease

Longyun WU,
Xiaolan LU^{,
,}

Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China

Research funding:

National Natural Science Foundation of China (82070587)

More Information

Corresponding author: LU Xiaolan xiaolan_lu@163.com (ORCID: 0000-0001-5745-6373)

摘要

摘要: 铁死亡是以铁依赖和脂质过氧化为特征的非凋亡性细胞死亡方式。非酒精性脂肪性肝病(NAFLD)是以脂肪浸润为主要病理特征，与胰岛素抵抗和遗传易感性密切相关的一类代谢性疾病。肝脏单纯脂肪变性向脂肪性肝炎转变的机制仍不清楚，有研究发现肝细胞性铁死亡可能是脂肪性肝炎炎症启动的触发因素。本综述重点关注铁代谢异常和脂质过氧化在促进NAFLD发生及发展中的作用，并归纳总结一些铁死亡相关抑制剂在NAFLD治疗中的应用前景。
- 铁死亡 /
- 铁代谢障碍 /
- 非酒精性脂肪性肝病 /
- 脂质过氧化作用 /
- 药物疗法
Abstract: Ferroptosis is a pattern of non-apoptotic cell death characterized by iron dependence and lipid peroxidation. Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease with fat infiltration as its main pathological feature, and it is closely associated with insulin resistance and genetic susceptibility. The mechanism of transition from hepatic steatosis alone to steatohepatitis remains unclear, and studies have shown that ferroptosis in hepatocytes may be the trigger for the inflammatory initiation of steatohepatitis. This article reviews the role of abnormal iron metabolism and lipid peroxidation in promoting the development and progression of NAFLD and summarizes the application prospect of ferroptosis-related inhibitors in the treatment of NAFLD.
- Ferroptosis /
- Iron Metabolism Disorders /
- Non-alcoholic Fatty Liver Disease /
- Lipid Peroxidation /
- Drug Therapy

HTML全文

图 1 铁死亡及其抑制剂在NAFLD中作用的模式

注：FSP1，铁死亡抑制蛋白1；SLC3A2，溶质载体家族3成员2; SLC7A11，溶质载体家族7成员11；PUFA-PL, 多不饱和脂肪酸-磷脂；PUFA-PL-OOH，多不饱和脂肪酸-磷脂乙醇胺过氧化氢；LOX，脂氧合酶；ACSL4，酰基辅酶A合成酶长链家族成员4；LPCAT3，溶血磷脂酰胆碱酰基转移酶3；GSSG，氧化型谷胱甘肽；GPX4，谷胱甘肽过氧化物酶4；BMP4, 骨形态发生蛋白4；Tβ4，胸腺素β4；DHODH，二氢乳清酸脱氢酶；DMF，富马酸二甲酯；GB，银杏内酯B；DA，脱氢松香酸；KP，山奈酚；NADP⁺，氧化烟酰胺腺嘌呤二核苷酸磷酸；NADPH，烟酰胺腺嘌呤二核苷酸。

Figure 1. The diagram delineating the role of ferroptosis and its inhibitors in NAFLD

下载: 全尺寸图片幻灯片

表 1 铁死亡、细胞凋亡、自噬、坏死性凋亡、细胞焦亡的形态学和生化特征

Table 1. Morphological and biochemical characteristics of ferroptosis, apoptosis, autophagy, necroptosis and pyroptosis

细胞死亡种类	形体学特征					生化特征
细胞死亡种类	细胞形态	细胞核	细胞器	细胞质膜	其他	生化特征
铁死亡	细胞变圆	细胞核正常、染色体无凝聚	线粒体体积变小，线粒体膜密度增加，外膜破裂、嵴缩小或消失	质膜无破裂		铁和ROS过载，脂质过氧化，MAPK激活，system Xc^-的抑制、胱氨酸的摄取减少、GSH的消耗，AA介质的释放
细胞凋亡	细胞体积变小	细胞核体积减少，核碎裂、染色质凝聚	线粒体结构无明显变化	细胞质膜出泡、细胞骨架解体	凋亡小体的形成	caspase的激活，寡核苷酸染色体DNA片段，PS暴露
自噬	初期细胞无变化	染色质缺乏凝聚	自噬溶酶体形成	质膜没有变化或可能出泡	自噬空泡的积累	LC3-Ⅰ向LC3-Ⅱ转化，底物降解，溶酶体活力增加
坏死性凋亡	细胞肿胀	染色质适当凝集	细胞器肿胀	质膜破裂	细胞组分进入微环境	ATP水平下降，DAMP的释放，PARP1的活化
焦亡	细胞肿胀	细胞核固缩	细胞器变形	质膜成孔	细胞组分进入微环境	炎性小体的形成，caspase- 1和Gasdermin D的激活，促炎因子的释放
注：ROS，活性氧；MAPK，促分裂原活化蛋白激酶；system Xc^-，抑制胱氨酸/谷氨酸逆转运体；GSH，谷胱甘肽; AA，花生四烯酸；PS，磷脂酰丝氨酸；LC，微管相关蛋白轻链；DAMP，损伤相关分子模式；PARP1，多聚腺苷二磷酸核糖聚合酶1。

下载: 导出CSV

表 2 铁死亡抑制剂在NAFLD治疗中的应用

Table 2. The inhibitors of ferroptosis in the treatment of NAFLD

药物	适应证¹⁾	作用机制	不良反应	研究现状	前景
维生素E	活检明确为NASH的、非糖尿病性、成年患者	抑制脂质氧化	可能增加出血性脑中风、前列腺癌的发生率	写入2018年NAFLD管理指南^[27]，推荐剂量：800 IU/d、口服	临床研究数据有限，谨慎用药
吡格列酮	肝活检已确诊的NASH患者(无论是否合并2型糖尿病)	抑制ACSL4	体质量的增加、骨质疏松的发生、膀胱癌患病率的升高	写入2018年NAFLD管理指南，未提供推荐剂量	临床研究数据有限，谨慎用药
艾地苯醌		提高GPX4的表达		有研究者建议也许可将该药扩大适应证，比如存在胰岛素抵抗的2型糖尿病和脂肪肝	进一步临床试验验证
富马酸二甲酯		降低细胞内ROS和脂质过氧化水平，防止GSH消耗和脂质过氧化物积累，促进GPX4的转录		动物实验阶段	开展临床试验
胸腺素β4		通过GPX4抑制铁死亡		动物实验阶段	开展临床试验
铁螯合剂		控制铁超载		尚无铁螯合剂在NAFLD中的研究报道	开展相关基础实验
Ferrostatin-1		抑制脂质过氧化		动物实验阶段	开展临床试验
Liproxstatin		抑制脂质过氧化		动物实验阶段	开展临床试验
山奈酚		抑制LPCAT3的表达		动物实验阶段	开展临床试验
银杏内酯B		激活Nrf2		动物实验阶段	开展临床试验
脱氢松香酸		激活Nrf2		动物实验阶段	开展临床试验
槲皮素		降低线粒体ROS		动物实验阶段	开展临床试验
注：1)此处的适应证主要针对NAFLD的治疗。

下载: 导出CSV

参考文献(50)

[1]	LI J, CAO F, YIN HL, et al. Ferroptosis: past, present and future[J]. Cell Death Dis, 2020, 11(2): 88. DOI: 10.1038/s41419-020-2298-2.
[2]	ESLAM M, SANYAL AJ, GEORGE J, et al. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020, 158(7): 1999-2014. e1. DOI: 10.1053/j.gastro.2019.11.312.
[3]	TSURUSAKI S, TSUCHIYA Y, KOUMURA T, et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis[J]. Cell Death Dis, 2019, 10(6): 449. DOI: 10.1038/s41419-019-1678-y.
[4]	EZQUERRO S, MOCHA F, FRÜHBECK G, et al. Ghrelin reduces TNF-α-induced human hepatocyte apoptosis, autophagy, and pyroptosis: role in obesity-associated NAFLD[J]. J Clin Endocrinol Metab, 2019, 104(1): 21-37. DOI: 10.1210/jc.2018-01171.
[5]	GAUL S, LESZCZYNSKA A, ALEGRE F, et al. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis[J]. J Hepatol, 2021, 74(1): 156-167. DOI: 10.1016/j.jhep.2020.07.041.
[6]	AFONSO MB, RODRIGUES PM, MATEUS-PINHEIRO M, et al. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease[J]. Gut, 2021, 70(12): 2359-2372. DOI: 10.1136/gutjnl-2020-321767.
[7]	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, 16(11): 1949-1973. DOI: 10.1080/15548627.2020.1712108.
[8]	LI Y, ZENG X, LU D, et al. Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis[J]. Hum Reprod, 2021, 36(4): 951-964. DOI: 10.1093/humrep/deaa363.
[9]	KWON MY, PARK E, LEE SJ, et al. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death[J]. Oncotarget, 2015, 6(27): 24393-24403. DOI: 10.18632/oncotarget.5162.
[10]	DONG H, QIANG Z, CHAI D, et al. Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1[J]. Aging (Albany NY), 2020, 12(13): 12943-12959. DOI: 10.18632/aging.103378.
[11]	GHANIM BY, QINNA NA. Nrf2/ARE axis signalling in hepatocyte cellular death[J]. Mol Biol Rep, 2022, 49(5): 4039-4053. DOI: 10.1007/s11033-022-07125-6.
[12]	VALENTI L, MOSCATIELLO S, VANNI E, et al. Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling-a propensity score-adjusted observational study[J]. QJM, 2011, 104(2): 141-149. DOI: 10.1093/qjmed/hcq170.
[13]	YANG WS, KIM KJ, GASCHLER MM, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci U S A, 2016, 113(34): E4966- E4975. DOI: 10.1073/pnas.1603244113.
[14]	DOLL S, PRONETH B, TYURINA YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13(1): 91-98. DOI: 10.1038/nchembio.2239.
[15]	XIANG H, SHAO M, LU Y, et al. Kaempferol alleviates steatosis and inflammation during early non-alcoholic steatohepatitis associated with liver X receptor α-lysophosphatidylcholine acyltransferase 3 signaling pathway[J]. Front Pharmacol, 2021, 12: 690736. DOI: 10.3389/fphar.2021.690736.
[16]	JIANG L, KON N, LI T, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545): 57-62. DOI: 10.1038/nature14344.
[17]	CARLSON BA, TOBE R, YEFREMOVA E, et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration[J]. Redox Biol, 2016, 9: 22-31. DOI: 10.1016/j.redox.2016.05.003.
[18]	WANG X, MA B, WEN X, et al. Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis[J]. Cell Death Discov, 2022, 8(1): 234. DOI: 10.1038/s41420-022-01011-7.
[19]	DOLL S, FREITAS FP, SHAH R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575(7784): 693-698. DOI: 10.1038/s41586-019-1707-0.
[20]	BERSUKER K, HENDRICKS JM, LI Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575(7784): 688-692. DOI: 10.1038/s41586-019-1705-2.
[21]	LI L, NG SR, COLÓN CI, et al. Identification of DHODH as a therapeutic target in small cell lung cancer[J]. Sci Transl Med, 2019, 11(517): eaaw7852. DOI: 10.1126/scitranslmed.aaw7852.
[22]	MAO C, LIU X, ZHANG Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer[J]. Nature, 2021, 593(7860): 586-590. DOI: 10.1038/s41586-021-03539-7.
[23]	MAO X, HUANG D, RAO C, et al. Enoyl coenzyme A hydratase 1 combats obesity and related metabolic disorders by promoting adipose tissue browning[J]. Am J Physiol Endocrinol Metab, 2020, 318(3): E318-E329. DOI: 10.1152/ajpendo.00424.2019.
[24]	LIU B, YI W, MAO X, et al. Enoyl coenzyme A hydratase 1 alleviates nonalcoholic steatohepatitis in mice by suppressing hepatic ferroptosis[J]. Am J Physiol Endocrinol Metab, 2021, 320(5): E925-E937. DOI: 10.1152/ajpendo.00614.2020.
[25]	SCHAUER PR, NOR HANIPAH Z, RUBINO F. Metabolic surgery for treating type 2 diabetes mellitus: Now supported by the world's leading diabetes organizations[J]. Cleve Clin J Med, 2017, 84(7 Suppl 1): S47-S56. DOI: 10.3949/ccjm.84.s1.06.
[26]	YOUNOSSI ZM, RATZIU V, LOOMBA R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial[J]. Lancet, 2019, 394(10215): 2184-2196. DOI: 10.1016/S0140-6736(19)33041-7.
[27]	CHALASANI N, YOUNOSSI Z, LAVINE JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases[J]. Hepatology, 2018, 67(1): 328-357. DOI: 10.1002/hep.29367.
[28]	IMAI H, MATSUOKA M, KUMAGAI T, et al. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis[J]. Curr Top Microbiol Immunol, 2017, 403: 143-170. DOI: 10.1007/82_2016_508.
[29]	BELL LN, WANG J, MURALIDHARAN S, et al. Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondi abetic patients with nonalcoholic steatohepatitis trial follow-up study[J]. Hepatology, 2012, 56(4): 1311-1318. DOI: 10.1002/hep.25805.
[30]	LAVINE JE, SCHWIMMER JB, van NATTA ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial[J]. JAMA, 2011, 305(16): 1659-1668. DOI: 10.1001/jama.2011.520.
[31]	KLEIN EA, THOMPSON IM Jr, TANGEN CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT)[J]. JAMA, 2011, 306(14): 1549-1556. DOI: 10.1001/jama.2011.1437.
[32]	SCHÜRKS M, GLYNN RJ, RIST PM, et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials[J]. BMJ, 2010, 341: c5702. DOI: 10.1136/bmj.c5702.
[33]	KUNG YA, CHIANG HJ, LI ML, et al. Acyl-coenzyme a synthetase long-chain family member 4 is involved in viral replication organelle formation and facilitates virus replication via ferroptosis[J]. mBio, 2022, 13(1): e0271721. DOI: 10.1128/mbio.02717-21.
[34]	CUSI K, ORSAK B, BRIL F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial[J]. Ann Intern Med, 2016, 165(5): 305-315. DOI: 10.7326/M15-1774.
[35]	AUBERT RE, HERRERA V, CHEN W, et al. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes[J]. Diabetes Obes Metab, 2010, 12(8): 716-721. DOI: 10.1111/j.1463-1326.2010.01225.x.
[36]	TANG H, SHI W, FU S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis[J]. Cancer Med, 2018, 7(4): 1070-1080. DOI: 10.1002/cam4.1354.
[37]	AVCI B, GÜNAYDIN C, GÜVENÇ T, et al. Idebenone ameliorates rotenone-induced parkinson's disease in rats through decreasing lipid peroxidation[J]. Neurochem Res, 2021, 46(3): 513-522. DOI: 10.1007/s11064-020-03186-w.
[38]	JIANG JX, TOMILOV A, MONTGOMERY C, et al. Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice[J]. J Biochem Mol Toxicol, 2021, 35(10): e22876. DOI: 10.1002/jbt.22876.
[39]	TOMILOV A, ALLEN S, HUI CK, et al. Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition[J]. Pharmacol Res, 2018, 137: 89-103. DOI: 10.1016/j.phrs.2018.09.024.
[40]	YAN N, XU Z, QU C, et al. Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway[J]. Int Immunopharmacol, 2021, 98: 107844. DOI: 10.1016/j.intimp.2021.107844.
[41]	VANANI AR, KALANTARI H, MAHDAVINIA M, et al. Dimethyl fumarate reduces oxidative stress, inflammation and fat deposition by modulation of Nrf2, SREBP-1c and NF-κB signaling in HFD fed mice[J]. Life Sci, 2021, 283: 119852. DOI: 10.1016/j.lfs.2021.119852.
[42]	QIU YB, WAN BB, LIU G, et al. Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis[J]. Respir Res, 2020, 21(1): 232. DOI: 10.1186/s12931-020-01500-2.
[43]	ZHU Z, ZHANG Y, HUANG X, et al. Thymosin beta 4 alleviates non-alcoholic fatty liver by inhibiting ferroptosis via up-regulation of GPX4[J]. Eur J Pharmacol, 2021, 908: 174351. DOI: 10.1016/j.ejphar.2021.174351.
[44]	KONTOGHIORGHE CN, KONTOGHIORGHES GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes[J]. Drug Des Devel Ther, 2016, 10: 465-481. DOI: 10.2147/DDDT.S79458.
[45]	WU S, YANG J, SUN G, et al. Macrophage extracellular traps aggravate iron overload-related liver ischaemia/reperfusion injury[J]. Br J Pharmacol, 2021, 178(18): 3783-3796. DOI: 10.1111/bph.15518.
[46]	LUO Y, CHEN H, LIU H, et al. Protective effects of ferroptosis inhibition on high fat diet-induced liver and renal injury in mice[J]. Int J Clin Exp Pathol, 2020, 13(8): 2041-2049.
[47]	QI J, KIM JW, ZHOU Z, et al. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice[J]. Am J Pathol, 2020, 190(1): 68-81. DOI: 10.1016/j.ajpath.2019.09.011.
[48]	YANG Y, CHEN J, GAO Q, et al. Study on the attenuated effect of Ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease[J]. Toxicology, 2020, 445: 152599. DOI: 10.1016/j.tox.2020.152599.
[49]	GAO G, XIE Z, LI EW, et al. Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis[J]. J Nat Med, 2021, 75(3): 540-552. DOI: 10.1007/s11418-021-01491-4.
[50]	JIANG JJ, ZHANG GF, ZHENG JY, et al. Targeting mitochondrial ROS-mediated ferroptosis by quercetin alleviates high-fat diet-induced hepatic lipotoxicity[J]. Front Pharmacol, 2022, 13: 876550. DOI: 10.3389/fphar.2022.876550.