沉默调节蛋白1在酒精性肝病中的作用机制及相关药物研究进展

刘甜恬; 刘江凯; 李素领; 刘靓; 张雅儒; 张建文; 李冰倩

doi:10.3969/j.issn.1001-5256.2022.12.030

沉默调节蛋白1在酒精性肝病中的作用机制及相关药物研究进展

DOI: 10.3969/j.issn.1001-5256.2022.12.030

1.
河南中医药大学第一临床医学院，郑州 450018
2.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

国家自然科学基金(联合基金) (U1504825);

河南省高等学校重点科研项目 (20A360014);

河南省中医药拔尖人才培养项目资助 (Yuwei Traditional Chinese Medicine 2021 No.15)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：刘甜恬负责课题设计，资料分析，撰写论文；李素领负责修改论文；刘靓、张雅儒、张建文、李冰倩参与收集及分析文献资料；刘江凯负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
刘江凯，xmlc001@126.com

计量
- 文章访问数: 1742
- HTML全文浏览量: 960
- PDF下载量: 77
- 被引次数: 0
出版历程
- 收稿日期: 2022-05-07
- 录用日期: 2022-06-17
- 出版日期: 2022-12-20

Advances in the mechanism of action of silent information regulator 1 in alcoholic liver disease and related pharmaceutical studies

1.
The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450018, China
2.
Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China

Research funding:

National Natural Science Foundation of China (Joint Fund) (U1504825);

Key Scientific Research Projects of Colleges and Universities in Henan Province (20A360014);

Henan Provincial Top talents training Program of Traditional Chinese Medicine (Yuwei Traditional Chinese Medicine 2021 No.15)

More Information

Corresponding author: LIU Jiangkai, xmlc001@126.com (ORCID: 0000-0002-1529-5089)

摘要

摘要: 酒精性肝病(ALD)是全球慢性肝病的主要病种之一，我国ALD发病率正逐年上升且呈年轻化发展态势。沉默调节蛋白1(SIRT1)是一种烟酰胺腺嘌呤二核苷酸依赖性的脱乙酰化酶，在细胞代谢、氧化应激、炎症反应等方面作用显著，有望成为ALD治疗新靶点。本文总结了SIRT1在ALD中的作用机制及相关药物研究，以期为进一步研究ALD发病机制及其潜在治疗靶标提供参考和策略。
- 酒精性肝病 /
- 沉默信息调节蛋白质类 /
- 炎症
Abstract: Alcoholic liver disease (ALD) is one of the main chronic liver diseases in the world, and the prevalence rate of ALD is increasing year by year in China, with a trend of earlier age of onset. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase and plays a significant role in cell metabolism, oxidative stress, and inflammation, and it is expected to become a new therapeutic target for ALD. This article reviews the mechanism of action of SIRT1 in ALD and related pharmaceutical studies, in order to provide a reference and strategies for further research on the pathogenesis of ALD and its potential therapeutic targets.
- Alcoholic Liver Disease /
- Silent Information Regulator Proteins /
- Inflammation

HTML全文

图 1 SIRT1调节ALD的机制

Figure 1. Mechanism of SIRT1 regulating ALD

下载: 全尺寸图片幻灯片

参考文献(46)

[1]	SEITZ HK, BATALLER R, CORTEZ-PINTO H, et al. Alcoholic liver disease[J]. Nat Rev DisPrimers, 2018, 4(1): 16. DOI: 10.1038/s41572-018-0014-7.
[2]	World Health Organization. Global status report on alcohol and health 2018[M]. World Health Organization, 2019.
[3]	WANG WJ, XIAO P, XU HQ, et al. Growing burden of alcoholic liver disease in China: A review[J]. World J Gastroenterol, 2019, 25(12): 1445-1456. DOI: 10.3748/wjg.v25.i12.1445.
[4]	LIU Y, SU L. Guidline for primary care of alcoholic liver disease(2019)[J]. J Clin Hepatol, 2021, 37(1): 36-40. DOI: 10.3969/j.issn.1001-5256.2021.01.008. 刘岩, 苏琳. 酒精性肝病基层诊疗指南(2019年)[J]. 临床肝胆病杂志, 2021, 37(1): 36-40. DOI: 10.3969/j.issn.1001-5256.2021.01.008.
[5]	HYUN J, HAN J, LEE C, et al. Pathophysiological aspects of alcohol metabolism in the liver[J]. Int J Mol Sci, 2021, 22(11): 5717. DOI: 10.3390/ijms22115717.
[6]	SONG Q, CHEN Y, WANG J, et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development[J]. J Hepatol, 2020, 73(4): 783-793. DOI: 10.1016/j.jhep.2020.04.038.
[7]	KANG H, PARK YK, LEE JY. Nicotinamide riboside, an NAD⁺ precursor, attenuates inflammation and oxidative stress by activating sirtuin 1 in alcohol-stimulated macrophages[J]. Lab Invest, 2021, 101(9): 1225-1237. DOI: 10.1038/s41374-021-00599-1.
[8]	YIN H, HU M, LIANG X, et al. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver[J]. Gastroenterology, 2014, 146(3): 801-811. DOI: 10.1053/j.gastro.2013.11.008.
[9]	CHEN C, ZHOU M, GE Y, et al. SIRT1 and aging related signaling pathways[J]. Mech Ageing Dev, 2020, 187: 111215. DOI: 10.1016/j.mad.2020.111215.
[10]	ZHOU Z, YE TJ, DECARO E, et al. Intestinal SIRT1 deficiency protects mice from ethanol-induced liver injury by mitigating ferroptosis[J]. Am J Pathol, 2020, 190(1): 82-92. DOI: 10.1016/j.ajpath.2019.09.012.
[11]	NAKAMURA K, ZHANG M, KAGEYAMA S, et al. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury[J]. J Hepatol, 2017, 67(6): 1232-1242. DOI: 10.1016/j.jhep.2017.08.010.
[12]	HERSKOVITS AZ, GUARENTE L. Sirtuin deacetylases in neurodegenerative diseases of aging[J]. Cell Res, 2013, 23(6): 746-758. DOI: 10.1038/cr.2013.70.
[13]	TANNO M, SAKAMOTO J, MIURA T, et al. Nucleocytoplasmic shuttling of the NAD⁺-dependent histone deacetylase SIRT1[J]. J Biol Chem, 2007, 282(9): 6823-6832. DOI: 10.1074/jbc.M609554200.
[14]	YANG X, DONG WB, LEI XP, et al. Resveratrol suppresses hyperoxia-induced nucleocytoplasmic shuttling of SIRT1 and ROS production in PBMC from preterm infants in vitro[J]. J Matern Fetal Neonatal Med, 2018, 31(9): 1142-1150. DOI: 10.1080/14767058.2017.1311310.
[15]	GOODMAN RP, MARKHARD AL, SHAH H, et al. Hepatic NADH reductive stress underlies common variation in metabolic traits[J]. Nature, 2020, 583(7814): 122-126. DOI: 10.1038/s41586-020-2337-2.
[16]	CUI X, CHEN Q, DONG Z, et al. Inactivation of Sirt1 in mouse livers protects against endotoxemic liver injury by acetylating and activating NF-κB[J]. Cell Death Dis, 2016, 7(10): e2403. DOI: 10.1038/cddis.2016.270.
[17]	DUAN FF, CHENG J, YANG S. Research progress on liver transplantation for alcoholic liver disease[J]. Organ Transplantation, 2020, 11(3): 413-418. DOI: 10.3969/j.issn.1674-7445.2020.03.016. 段方方, 成军, 杨松. 酒精性肝病肝移植的研究进展[J]. 器官移植, 2020, 11(3): 413-418. DOI: 10.3969/j.issn.1674-7445.2020.03.016.
[18]	NOWAK AJ, RELJA B. The impact of acute or chronic alcohol intake on the NF-κB signaling pathway in alcohol-related liver disease[J]. Int J Mol Sci, 2020, 21(24): 9407. DOI: 10.3390/ijms21249407.
[19]	XIONG X, YU J, FAN R, et al. NAMPT overexpression alleviates alcohol-induced hepatic steatosis in mice[J]. PLoS One, 2019, 14(2): e0212523. DOI: 10.1371/journal.pone.0212523.
[20]	KANG H, KIM MB, PARK YK, et al. A mouse model of the regression of alcoholic hepatitis: Monitoring the regression of hepatic steatosis, inflammation, oxidative stress, and NAD⁺ metabolism upon alcohol withdrawal[J]. J Nutr Biochem, 2022, 99: 108852. DOI: 10.1016/j.jnutbio.2021.108852.
[21]	LIU CY, WANG M, YU HM, et al. Ferroptosis is involved in alcohol-induced cell death in vivo and in vitro[J]. Biosci Biotechnol Biochem, 2020, 84(8): 1621-1628. DOI: 10.1080/09168451.2020.1763155.
[22]	YOU M, ARTEEL GE. Effect of ethanol on lipid metabolism[J]. J Hepatol, 2019, 70(2): 237-248. DOI: 10.1016/j.jhep.2018.10.037.
[23]	PI A, JIANG K, DING Q, et al. Alcohol abstinence rescues hepatic steatosis and liver injury via improving metabolic reprogramming in chronic alcohol-fed mice[J]. Front Pharmacol, 2021, 12: 752148. DOI: 10.3389/fphar.2021.752148.
[24]	HOU Y, SU B, CHEN P, et al. Association of SIRT1 gene polymorphism and its expression for the risk of alcoholic fatty liver disease in the Han population[J]. Hepatol Int, 2018, 12(1): 56-66. DOI: 10.1007/s12072-017-9836-8.
[25]	SILVA J, SPATZ MH, FOLK C, et al. Dihydromyricetin improves mitochondrial outcomes in the liver of alcohol-fed mice via the AMPK/Sirt-1/PGC-1α signaling axis[J]. Alcohol, 2021, 91: 1-9. DOI: 10.1016/j.alcohol.2020.10.002.
[26]	NAGAPPAN A, KIM JH, JUNG DY, et al. Cryptotanshinone from the salvia miltiorrhiza bunge attenuates ethanol-induced liver injury by activation of AMPK/SIRT1 and Nrf2 signaling pathways[J]. Int J Mol Sci, 2019, 21(1): 265. DOI: 10.3390/ijms21010265.
[27]	LEE HI, YUN KW, SEO KI, et al. Scopoletin prevents alcohol-induced hepatic lipid accumulation by modulating the AMPK-SREBP pathway in diet-induced obese mice[J]. Metabolism, 2014, 63(4): 593-601. DOI: 10.1016/j.metabol.2014.01.003.
[28]	PONUGOTI B, KIM DH, XIAO Z, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism[J]. J Biol Chem, 2010, 285(44): 33959-33970. DOI: 10.1074/jbc.M110.122978.
[29]	BI L, JIANG Z, ZHOU J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver[J]. Alcohol Alcohol, 2015, 50(2): 146-151. DOI: 10.1093/alcalc/agu102.
[30]	LI Y, ZHOU J. Roles of silent information regulator 1-serine/arginine-rich splicing factor 10-lipin 1 axis in the pathogenesis of alcohol fatty liver disease[J]. Exp Biol Med (Maywood), 2017, 242(11): 1117-1125. DOI: 10.1177/1535370217707729.
[31]	YIN H, HU M, ZHANG R, et al. MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1[J]. J Biol Chem, 2012, 287(13): 9817-9826. DOI: 10.1074/jbc.M111.333534.
[32]	YAO YL, HAN X, LI ZM, et al. Acanthoic acid can partially prevent alcohol exposure-induced liver lipid deposition and inflammation[J]. Front Pharmacol, 2017, 8: 134. DOI: 10.3389/fphar.2017.00134.
[33]	CHEN X, XU Y, DENNING KL, et al. PPARα agonist WY-14, 643 enhances ethanol metabolism in mice: Role of catalase[J]. Free Radic Biol Med, 2021, 169: 283-293. DOI: 10.1016/j.freeradbiomed.2021.04.018.
[34]	YUE R, CHEN GY, XIE G, et al. Activation of PPARα-catalase pathway reverses alcoholic liver injury via upregulating NAD synthesis and accelerating alcohol clearance[J]. Free Radic Biol Med, 2021, 174: 249-263. DOI: 10.1016/j.freeradbiomed.2021.08.005.
[35]	ATTAL N, MARRERO E, THOMPSON KJ, et al. Cytochrome P4502E1-dependent hepaticethanol metabolism induces fatty acid-binding protein 4 and steatosis[J]. Alcohol Clin Exp Res, 2022, 46(6): 928-940. DOI: 10.1111/acer.14828.
[36]	CHEN H, SHEN F, SHERBAN A, et al. DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease[J]. Hepatology, 2018, 68(2): 496-514. DOI: 10.1002/hep.29849.
[37]	LEE SE, KOH H, JOO DJ, et al. Induction of SIRT1 by melatonin improves alcohol-mediated oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway[J]. J Pineal Res, 2020, 68(3): e12638. DOI: 10.1111/jpi.12638.
[38]	ZHOU Y, WANG S, WAN T, et al. Cyanidin-3-O-β-glucoside inactivates NLRP3 inflammasome and alleviates alcoholic steatohepatitis via SirT1/NF-κB signaling pathway[J]. Free Radic Biol Med, 2020, 160: 334-341. DOI: 10.1016/j.freeradbiomed.2020.08.006.
[39]	RAMIREZ T, LI YM, YIN S, et al. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression[J]. J Hepatol, 2017, 66(3): 601-609. DOI: 10.1016/j.jhep.2016.11.004.
[40]	WU Y, LIU X, ZHOU Q, et al. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion[J]. Toxicol Appl Pharmacol, 2015, 289(2): 163-176. DOI: 10.1016/j.taap.2015.09.028.
[41]	KIM MJ, AN HJ, KIM DH, et al. Novel SIRT1 activator MHY2233 improves glucose tolerance and reduces hepatic lipid accumulation in db/db mice[J]. Bioorg Med Chem Lett, 2018, 28(4): 684-688. DOI: 10.1016/j.bmcl.2018.01.021.
[42]	LIU X, ZHAO H, LUO C, et al. Acetaminophen responsive miR-19b modulates SIRT1/Nrf2 signaling pathway in drug-induced hepatotoxicity[J]. Toxicol Sci, 2019, 170(2): 476-488. DOI: 10.1093/toxsci/kfz095.
[43]	RAWAT D, CHHONKER SK, NAIK RA, et al. Modulation of antioxidant enzymes, SIRT1 and NF-κB by resveratrol and nicotinamide in alcohol-aflatoxin B1-induced hepatocellular carcinoma[J]. J Biochem Mol Toxicol, 2021, 35(1): e22625. DOI: 10.1002/jbt.22625.
[44]	ZHOU YN, XU PJ, DENG CF, et al. Chrysin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK signaling pathway[J]. Chin Pharmacol Bull, 2022, 38(1): 159-160. DOI: 10.3969/j.issn.1001-1978.2022.01.028. 周禹柠, 徐培杰, 邓楚凡, 等. 白杨素通过SIRT1/AMPK信号通路缓解乙醇诱导的酒精性肝损伤[J]. 中国药理学通报, 2022, 38(1): 159-160. DOI: 10.3969/j.issn.1001-1978.2022.01.028.
[45]	YANG T, SONG HP, CHEN Z, et al. Effect and mechanism of Yinchenhao decoction on acute alcoholic liver injury based on SIRT1/AMPK signaling pathway[J]. Pharmocol Clin Chin Mater Med, 2022, 38(1): 36-40. DOI: 10.13412/j.cnki.zyyl.zyyl.2022.01.019. 杨焘, 宋厚盼, 陈哲, 等. 基于SIRT1/AMPK信号通路探讨茵陈蒿汤治疗急性酒精性肝损伤的效应及机制[J]. 中药药理与临床, 2022, 38(1): 36-40. DOI: 10.13412/j.cnki.zyyl.2022.01.019.
[46]	WEI Z, JIA J, HENG G, et al. Sirtuin-1/Mitochondrial ribosomal protein S5 axis enhances the metabolic flexibility of liver cancer stem cells[J]. Hepatology, 2019, 70(4): 1197-1213. DOI: 10.1002/hep.30622.