非酒精性脂肪肝病的治疗模式和潜在疗法

李凤; 李茂微; 王雨杉

doi:10.12449/JCH241025

非酒精性脂肪肝病的治疗模式和潜在疗法

DOI: 10.12449/JCH241025

李凤^1a, , ,,
李茂微²,
王雨杉^1b

1a.
吉林省一汽总医院药物/医疗器械临床试验机构办公室，长春 130000
1b.
吉林省一汽总医院药品管理部，长春 130000
2.
长春市第二医院药剂科，长春 130000

基金项目:

吉林省科技厅项目 (20210401054YY)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李凤负责资料分析与撰写论文并最终定稿；李茂微、王雨杉协助收集资料并修改论文。

详细信息

通信作者:
李凤， 18943994025@163.com （ORCID： 0009-0009-8760-3675）

计量
- 文章访问数: 12
- HTML全文浏览量: 12
- PDF下载量: 0
- 被引次数: 0
出版历程
- 收稿日期: 2024-02-21
- 录用日期: 2024-03-26
- 出版日期: 2024-10-25

Therapeutic paradigms and potential therapies for nonalcoholic steatohepatitis

Feng LI^{1a
, ,
,},
Maowei LI²,
Yushan WANG^1b

1a.
Office of Clinical Trial Institutions for Drug and Medical Devices，The FAW General Hospital of Jilin Province，Changchun 130000，China
1b.
Department of Drug Management，The FAW General Hospital of Jilin Province，Changchun 130000，China
2.
Department of Pharmacy，The Second Hospital of Changchun，Changchun 130000，China

Research funding:

Jilin Provincial Department of Science and Technology Project (20210401054YY)

More Information

Corresponding author: LI Feng， 18943994025@163.com （ORCID： 0009-0009-8760-3675）

摘要

摘要: 近年来，非酒精性脂肪性肝炎（NASH）在流行病学、发病机理和确定治疗靶点等方面取得了稳步进展，但在治疗药物开发领域却进展缓慢。本文综述了生活方式干预、手术方法、肠道微生物群和药物治疗在治疗NASH方面的进展，重点关注胰岛素增敏剂、抗氧化剂、降胆固醇药物、甲状腺激素类似物、肠促胰岛素和细胞因子等药物对治疗NASH的作用，以期为未来治疗NASH提供更多的方法和选择。
- 非酒精性脂肪性肝病 /
- 脂肪肝 /
- 治疗学
Abstract: In recent years， steady progress has been made in the epidemiology， pathogenesis， and therapeutic targets of nonalcoholic steatohepatitis （NASH）， while there has been slow progress in the field of therapeutic drug development. This article reviews the advances in lifestyle intervention， surgical methods， gut microbiota， and drugs in the treatment of NASH， especially the role of insulin sensitizers， antioxidants， cholesterol-lowering drugs， thyroid hormone mimetics， incretins， and cytokines in the treatment of NASH， in order to provide more methods and options for the treatment of NASH in the future.
- Non-alcoholic Fatty Liver Disease /
- Fatty Liver /
- Therapeutics

HTML全文

参考文献(49)

[1]	ZEIGERER A. NAFLD-A rising metabolic disease[J]. Mol Metab, 2021, 50: 101274. DOI: 10.1016/j.molmet.2021.101274.
[2]	WANG YK, WEI SY, LIU C, et al. A new definition of fatty liver disease: from nonalcoholic fatty liver disease to metabolic associated fatty liver disease[J]. Chin J Dig Surg, 2023, 22( S1): 117- 121. DOI: 10.3760/cma.j.cn115610-20230909-00080. 王永康, 魏诗雨, 刘昌, 等. 脂肪性肝病新定义:从非酒精性脂肪性肝病到代谢功能障碍相关脂肪性肝病[J]. 中华消化外科杂志, 2023, 22( S1): 117- 121. DOI: 10.3760/cma.j.cn115610-20230909-00080.
[3]	DUELL PB, WELTY FK, MILLER M, et al. Nonalcoholic fatty liver disease and cardiovascular risk: A scientific statement from the American heart association[J]. Arterioscler Thromb Vasc Biol, 2022, 42( 6): e168- e185. DOI: 10.1161/ATV.0000000000000153.
[4]	CIARDULLO S, BALLABENI C, TREVISAN R, et al. Liver stiffness, albuminuria and chronic kidney disease in patients with NAFLD: A systematic review and meta-analysis[J]. Biomolecules, 2022, 12( 1): 105. DOI: 10.3390/biom12010105.
[5]	BJÖRKSTRÖM K, WIDMAN L, HAGSTRÖM H. Risk of hepatic and extrahepatic cancer in NAFLD: A population-based cohort study[J]. Liver Int, 2022, 42( 4): 820- 828. DOI: 10.1111/liv.15195.
[6]	ESTES C, ANSTEE QM, ARIAS-LOSTE MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030[J]. J Hepatol, 2018, 69( 4): 896- 904. DOI: 10.1016/j.jhep.2018.05.036.
[7]	POUWELS S, SAKRAN N, GRAHAM Y, et al. Non-alcoholic fatty liver disease(NAFLD): A review of pathophysiology, clinical management and effects of weight loss[J]. BMC Endocr Disord, 2022, 22( 1): 63. DOI: 10.1186/s12902-022-00980-1.
[8]	HYDES TJ, RAVI S, LOOMBA R, et al. Evidence-based clinical advice for nutrition and dietary weight loss strategies for the management of NAFLD and NASH[J]. Clin Mol Hepatol, 2020, 26( 4): 383- 400. DOI: 10.3350/cmh.2020.0067.
[9]	YOUNOSSI ZM, COREY KE, LIM JK. AGA clinical practice update on lifestyle modification using diet and exercise to achieve weight loss in the management of nonalcoholic fatty liver disease: Expert review[J]. Gastroenterology, 2021, 160( 3): 912- 918. DOI: 10.1053/j.gastro.2020.11.051.
[10]	HANNAH WN Jr, HARRISON SA. Effect of weight loss, diet, exercise, and bariatric surgery on nonalcoholic fatty liver disease[J]. Clin Liver Dis, 2016, 20( 2): 339- 350. DOI: 10.1016/j.cld.2015.10.008.
[11]	SUN J, RUAN YT, XU NN, et al. The effect of dietary carbohydrate and calorie restriction on weight and metabolic health in overweight/obese individuals: A multi-center randomized controlled trial[J]. BMC Med, 2023, 21( 1): 192. DOI: 10.1186/s12916-023-02869-9.
[12]	WEI XY, LIN BQ, HUANG Y, et al. Effects of time-restricted eating on nonalcoholic fatty liver disease: The TREATY-FLD randomized clinical trial[J]. JAMA Netw Open, 2023, 6( 3): e233513. DOI: 10.1001/jamanetworkopen.2023.3513.
[13]	CASTAGNETO-GISSEY L, CASELLA-MARIOLO J, MINGRONE G. Bariatric/metabolic surgery[J]. Handb Exp Pharmacol, 2022, 274: 371- 386. DOI: 10.1007/164_2021_565.
[14]	VERRASTRO O, PANUNZI S, CASTAGNETO-GISSEY L, et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis(BRAVES): A multicentre, open-label, randomised trial[J]. Lancet, 2023, 401( 10390): 1786- 1797. DOI: 10.1016/S0140-6736(23)00634-7.
[15]	TILG H, ADOLPH TE, TRAUNER M. Gut-liver axis: Pathophysiological concepts and clinical implications[J]. Cell Metab, 2022, 34( 11): 1700- 1718. DOI: 10.1016/j.cmet.2022.09.017.
[16]	LIU LL, ZHANG JH, CHENG Y, et al. Gut microbiota: A new target for T2DM prevention and treatment[J]. Front Endocrinol(Lausanne), 2022, 13: 958218. DOI: 10.3389/fendo.2022.958218.
[17]	ALVES CC, WAITZBERG DL, de ANDRADE LS, et al. Prebiotic and synbiotic modifications of beta oxidation and lipogenic gene expression after experimental hypercholesterolemia in rat liver[J]. Front Microbiol, 2017, 8: 2010. DOI: 10.3389/fmicb.2017.02010.
[18]	XUE LF, DENG ZL, LUO WH, et al. Effect of fecal microbiota transplantation on non-alcoholic fatty liver disease: A randomized clinical trial[J]. Front Cell Infect Microbiol, 2022, 12: 759306. DOI: 10.3389/fcimb.2022.759306.
[19]	SAKURAI Y, KUBOTA N, YAMAUCHI T, et al. Role of insulin resistance in MAFLD[J]. Int J Mol Sci, 2021, 22( 8): 4156. DOI: 10.3390/ijms22084156.
[20]	BELL DSH, JERKINS T. In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome[J]. Diabetes Obes Metab, 2023, 25( 11): 3093- 3102. DOI: 10.1111/dom.15222.
[21]	LEWIS J, HABEL L, QUESENBERRY C, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes[J]. JAMA, 2015, 314( 3): 265- 77. DOI: 10.1001/jama.2015.7996.
[22]	WABITSCH S, MCCALLEN JD, KAMENYEVA O, et al. Metformin treatment rescues CD8⁺ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD[J]. J Hepatol, 2022, 77( 3): 748- 760. DOI: 10.1016/j.jhep.2022.03.010.
[23]	HARRISON SA, ALKHOURI N, DAVISON BA, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study[J]. J Hepatol, 2020, 72( 4): 613- 626. DOI: 10.1016/j.jhep.2019.10.023.
[24]	CHEN Z, TIAN RF, SHE ZG, et al. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease[J]. Free Radic Biol Med, 2020, 152: 116- 141. DOI: 10.1016/j.freeradbiomed.2020.02.025.
[25]	NAGASHIMADA M, OTA T. Role of vitamin E in nonalcoholic fatty liver disease[J]. IUBMB Life, 2019, 71( 4): 516- 522. DOI: 10.1002/iub.1991.
[26]	SANYAL AJ, CHALASANI N, KOWDLEY KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis[J]. N Engl J Med, 2010, 362( 18): 1675- 1685. DOI: 10.1056/NEJMoa0907929.
[27]	LOH WQ, YOUN J, SEOW WJ. Vitamin E intake and risk of prostate cancer: A meta-analysis[J]. Nutrients, 2022, 15( 1): 14. DOI: 10.3390/nu15010014.
[28]	ĆULAFIĆ M, VEZMAR-KOVAČEVIĆ S, DOPSAJ V, et al. Pentoxifylline with metformin treatment improves biochemical parameters in patients with nonalcoholic steatohepatitis[J]. J Med Biochem, 2020, 39( 3): 290- 298. DOI: 10.2478/jomb-2019-0043.
[29]	ZHU XX, WU M, WANG H, et al. Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: A double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study[J]. Expert Opin Investig Drugs, 2021, 30( 5): 579- 589. DOI: 10.1080/13543784.2021.1900822.
[30]	HU Y, LI HJ, ZHANG H, et al. ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial[J]. Nat Commun, 2023, 14( 1): 6409. DOI: 10.1038/s41467-023-42162-0.
[31]	SAFADI R, KONIKOFF FM, MAHAMID M, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease[J]. Clin Gastroenterol Hepatol, 2014, 12( 12): 2085- 2091. e 1. DOI: 10.1016/j.cgh.2014.04.038.
[32]	MALIK A, NADEEM M, AMJAD W, et al. Effects of Aramchol in patients with nonalcoholic fatty liver disease(NAFLD). A systematic review and meta-analysis[J]. Prz Gastroenterol, 2023, 18( 1): 67- 75. DOI: 10.5114/pg.2022.113573.
[33]	WANG CE, XU WT, GONG J, et al. Research progress on the treatment of non-alcoholic fatty liver disease[J]. Clin J Med Offic, 2022, 50( 9): 897- 899, 903. DOI: 10.16680/j.1671-3826.2022.09.06. 王彩娥, 许文涛, 宫建, 等. 非酒精性脂肪性肝病治疗研究进展[J]. 临床军医杂志, 2022, 50( 9): 897- 899, 903. DOI: 10.16680/j.1671-3826.2022.09.06.
[34]	KANNT A, WOHLFART P, MADSEN AN, et al. Activation of thyroid hormone receptor-β improved disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis[J]. Br J Pharmacol, 2021, 178( 12): 2412- 2423. DOI: 10.1111/bph.15427.
[35]	MAVROMATI M, JORNAYVAZ FR. Hypothyroidism-associated dyslipidemia: Potential molecular mechanisms leading to NAFLD[J]. Int J Mol Sci, 2021, 22( 23): 12797. DOI: 10.3390/ijms222312797.
[36]	HU LY, GU YP, LIANG J, et al. Discovery of highly potent and selective thyroid hormone receptor β agonists for the treatment of nonalcoholic steatohepatitis[J]. J Med Chem, 2023, 66( 5): 3284- 3300. DOI: 10.1021/acs.jmedchem.2c01669.
[37]	KARIM G, BANSAL MB. Resmetirom: An orally administered, smallmolecule, liver-directed, β-selective THR agonist for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis[J]. touchREV Endocrinol, 2023, 19( 1): 60- 70. DOI: 10.17925/EE.2023.19.1.60.
[38]	HARRISON SA, BEDOSSA P, GUY CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis[J]. N Engl J Med, 2024, 390( 6): 497- 509. DOI: 10.1056/NEJMoa2309000.
[39]	LOOMBA R, NEUTEL J, BERNARD D, et al. VK2809, a novel liver-directed thyroid receptor beta agonist, significantly reduces liver fat in patients with non-alcoholic fatty liver disease: a phase 2 randomized, placebo-controlled trial[J]. Hepatology, 2018,( 6): 68. DOI: 10.1016/s0168-8278(20)30652-8.
[40]	LI QX, GAO H, GUO YX, et al. GLP-1 and underlying beneficial actions in Alzheimer’s disease, hypertension, and NASH[J]. Front Endocrinol, 2021, 12: 721198. DOI: 10.3389/fendo.2021.721198.
[41]	BERNSMEIER C, MEYER-GERSPACH AC, BLASER LS, et al. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease[J]. PLoS One, 2014, 9( 1): e87488. DOI: 10.1371/journal.pone.0087488.
[42]	NEWSOME PN, BUCHHOLTZ K, CUSI K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis[J]. N Engl J Med, 2021, 384( 12): 1113- 1124. DOI: 10.1056/NEJMoa2028395.
[43]	JASTREBOFF AM, KAPLAN LM, FRÍAS JP, et al. Triple-hormone-receptor agonist retatrutide for obesity- A phase 2 trial[J]. N Engl J Med, 2023, 389( 6): 514- 526. DOI: 10.1056/NEJMoa2301972.
[44]	DUAN YM, PAN XF, LUO JY, et al. Association of inflammatory cytokines with non-alcoholic fatty liver disease[J]. Front Immunol, 2022, 13: 880298. DOI: 10.3389/fimmu.2022.880298.
[45]	FONTES-CAL TCM, MATTOS RT, MEDEIROS NI, et al. Crosstalk between plasma cytokines, inflammation, and liver damage as a new strategy to monitoring NAFLD progression[J]. Front Immunol, 2021, 12: 708959. DOI: 10.3389/fimmu.2021.708959.
[46]	ALAAEDDINE N, SIDAOUI J, HILAL G, et al. TNF-α messenger ribonucleic acid(mRNA) in patients with nonalcoholic steatohepatitis[J]. Eur Cytokine Netw, 2012, 23( 3): 107- 111. DOI: 10.1684/ecn.2012.0313.
[47]	AHMED H, UMAR MI, IMRAN S, et al. TGF-β1 signaling can worsen NAFLD with liver fibrosis backdrop[J]. Exp Mol Pathol, 2022, 124: 104733. DOI: 10.1016/j.yexmp.2021.104733.
[48]	WIDJAJA AA, SINGH BK, ADAMI E, et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis[J]. Gastroenterology, 2019, 157( 3): 777- 792. e 14. DOI: 10.1053/j.gastro.2019.05.002.
[49]	ANSTEE QM, NEUSCHWANDER-TETRI BA, WAI-SUN WONG V, et al. Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA phase Ⅲ randomized study[J]. Clin Gastroenterol Hepatol, 2024, 22( 1): 124- 134. e 1. DOI: 10.1016/j.cgh.2023.04.003.