他汀类药物在慢性肝病中的作用

杨希坤; 李晖; 曾子键; 吴旋; 王凯鑫

doi:10.12449/JCH241029

他汀类药物在慢性肝病中的作用

DOI: 10.12449/JCH241029

杨希坤^{1, 2},
李晖^1, , ,,
曾子键^{1, 2},
吴旋^{1, 2},
王凯鑫^{1, 2}

1.
成都中医药大学附属医院中心实验室，成都 610072
2.
成都中医药大学临床医学院，成都 610072

基金项目:

国家自然科学基金面上项目 (82274323)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：杨希坤负责撰写论文；曾子键、吴旋、王凯鑫参与查找文献，修改论文；李晖负责拟定写作思路，指导论文撰写并最后定稿。

详细信息

通信作者:
李晖， 1400124746@qq.com （ORCID： 0000-0002-5919-1396）

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- 文章访问数: 155
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- PDF下载量: 23
- 被引次数: 0
出版历程
- 收稿日期: 2024-02-18
- 录用日期: 2024-04-17
- 出版日期: 2024-10-25

Role of statins in chronic liver disease

Xikun YANG^{1, 2},
Hui LI^{1
, ,
,},
Zijian ZENG^{1, 2},
Xuan WU^{1, 2},
Kaixin WANG^{1, 2}

1.
Central Laboratory，The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine，Chengdu 610072，China
2.
School of Clinical Medicine，Chengdu University of Traditional Chinese Medicine，Chengdu 610072，China

Research funding:

General Project of National Natural Science Foundation of China (82274323)

More Information

Corresponding author: LI Hui， 1400124746@qq.com （ORCID： 0000-0002-5919-1396）

摘要

摘要: 慢性肝病是肝脏由炎症、纤维化，向肝硬化、肝癌进展的“魔鬼三部曲”，是全球肝病科医生面临的巨大挑战。他汀类药物自问世以来，在心血管疾病和高脂血症治疗中发挥了巨大作用，近年来其同样显示出在慢性肝病中具有改善肝脂肪变性、抗炎、调节肝星状细胞表型、降低门静脉压力、改善肝脏微循环等关键环节的重要潜力。本文综述了他汀类药物在慢性肝病基础和临床研究中的最新进展，为慢性肝病的研究和防治提供新的见解。
- 羟甲基戊二酰基CoA还原酶抑制剂 /
- 肝纤维化 /
- 肝硬化 /
- 癌，肝细胞
Abstract: Chronic liver disease is the “devil’s trilogy” in which the liver progresses from inflammation and fibrosis to liver cirrhosis and hepatocellular carcinoma， which poses a great challenge for hepatologists worldwide. Statins have played a significant role in the treatment of cardiovascular diseases and hyperlipidemia since their introduction， and in recent years， they have also demonstrated the potential to improve hepatic steatosis， exert an anti-inflammatory effect， regulate the phenotype of hepatic stellate cells， reduce portal venous pressure， and improve hepatic microcirculation in chronic liver disease. This article reviews the latest advances in the basic and clinical studies of statins in chronic liver disease， in order to provide new insights into the research， prevention， and treatment of chronic liver disease.
- Hydroxymethylglutaryl-CoA Reductase Inhibitors /
- Hepatic Fibrosis /
- Liver Cirrhosis /
- Carcinoma， Hepatocellular

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参考文献(47)

[1]	GERMAN CA, LIAO JK. Understanding the molecular mechanisms of statin pleiotropic effects[J]. Arch Toxicol, 2023, 97( 6): 1529- 1545. DOI: 10.1007/s00204-023-03492-6.
[2]	LI Z, WEI D, WAN MX, et al. Research progress on drug-induced liver injury induced by statins[J]. Drug Evaluat Res 2024, 47( 5): 941- 950. DOI: 10.7501/j.issn.1674-6376.2024.05.004. 李智, 魏栋, 万梅绪, 等. 他汀类药物致药物性肝损伤的研究进展[J]. 药物评价研究, 2024, 47( 5): 941- 950. DOI: 10.7501/j.issn.1674-6376.2024.05.004.
[3]	AYADA I, VAN KLEEF LA, ZHANG H, et al. Dissecting the multifaceted impact of statin use on fatty liver disease: A multidimensional study[J]. EBioMedicine, 2023, 87: 104392. DOI: 10.1016/j.ebiom.2022.104392.
[4]	GAO X, NAN Y, ZHAO YL, et al. Atorvastatin reduces lipid accumulation in the liver by activating protein kinase A-mediated phosphorylation of perilipin 5[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2017, 1862( 12): 1512- 1519. DOI: 10.1016/j.bbalip.2017.09.007.
[5]	WANG XB, CAI BS, YANG XM, et al. Cholesterol stabilizes TAZ in hepatocytes to promote experimental non-alcoholic steatohepatitis[J]. Cell Metab, 2020, 31( 5): 969- 986. e 7. DOI: 10.1016/j.cmet.2020.03.010.
[6]	CERDA A, BORTOLIN RH, MANRIQUEZ V, et al. Effect of statins on lipid metabolism-related microRNA expression in HepG2 cells[J]. Pharmacol Rep, 2021, 73( 3): 868- 880. DOI: 10.1007/s43440-021-00241-3.
[7]	ZHANG WW, YANG XX, CHEN YL, et al. Activation of hepatic Nogo-B receptor expression-a new anti-liver steatosis mechanism of statins[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2018, 1863( 2): 177- 190. DOI: 10.1016/j.bbalip.2017.12.002.
[8]	DEHNAVI S, KIANI A, SADEGHI M, et al. Targeting AMPK by statins: A potential therapeutic approach[J]. Drugs, 2021, 81( 8): 923- 933. DOI: 10.1007/s40265-021-01510-4.
[9]	LASTUVKOVA H, FARADONBEH FA, SCHREIBEROVA J, et al. Atorvastatin modulates bile acid homeostasis in mice with diet-induced nonalcoholic steatohepatitis[J]. Int J Mol Sci, 2021, 22( 12): 6468. DOI: 10.3390/ijms22126468.
[10]	INIA JA, STOKMAN G, PIETERMAN EJ, et al. Atorvastatin attenuates diet-induced non-alcoholic steatohepatitis in APOE*3-leiden mice by reducing hepatic inflammation[J]. Int J Mol Sci, 2023, 24( 9): 7818. DOI: 10.3390/ijms24097818.
[11]	NABIH ES, EL-KHARASHI OA. Targeting HMGB1/TLR4 axis and miR-21 by rosuvastatin: Role in alleviating cholestatic liver injury in a rat model of bile duct ligation[J]. Naunyn Schmiedebergs Arch Pharmacol, 2019, 392( 1): 37- 43. DOI: 10.1007/s00210-018-1560-y.
[12]	GONG J, TU W, LIU J, et al. Hepatocytes: A key role in liver inflammation[J]. Front Immunol, 2022, 13: 1083780. DOI: 10.3389/fimmu.2022.1083780.
[13]	RODRIGUES G, MOREIRA AJ, BONA S, et al. Simvastatin reduces hepatic oxidative stress and endoplasmic reticulum stress in nonalcoholic steatohepatitis experimental model[J]. Oxid Med Cell Longev, 2019, 2019: 3201873. DOI: 10.1155/2019/3201873.
[14]	PARK HS, JANG JE, KO MS, et al. Statins increase mitochondrial and peroxisomal fatty acid oxidation in the liver and prevent non-alcoholic steatohepatitis in mice[J]. Diabetes Metab J, 2016, 40( 5): 376- 385. DOI: 10.4093/dmj.2016.40.5.376.
[15]	PEREIRA ENGDS, ARAUJO BP, RODRIGUES KL, et al. Simvastatin improves microcirculatory function in nonalcoholic fatty liver disease and downregulates oxidative and ALE-RAGE stress[J]. Nutrients, 2022, 14( 3): 716. DOI: 10.3390/nu14030716.
[16]	MARINHO TS, KAWASAKI A, BRYNTESSON M, et al. Rosuvastatin limits the activation of hepatic stellate cells in diet-induced obese mice[J]. Hepatol Res, 2017, 47( 9): 928- 940. DOI: 10.1111/hepr.12821.
[17]	MARRONE G, MAESO-DÍAZ R, GARCÍA-CARDENA G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: Behind the molecular mechanisms of statins[J]. Gut, 2015, 64( 9): 1434- 1443. DOI: 10.1136/gutjnl-2014-308338.
[18]	KITSUGI K, NORITAKE H, MATSUMOTO M, et al. Simvastatin inhibits hepatic stellate cells activation by regulating the ferroptosis signaling pathway[J]. Biochim Biophys Acta Mol Basis Dis, 2023, 1869( 7): 166750. DOI: 10.1016/j.bbadis.2023.166750.
[19]	BRAVO M, RAURELL I, HIDE D, et al. Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH[J]. Sci Rep, 2019, 9( 1): 20183. DOI: 10.1038/s41598-019-56366-2.
[20]	CHONG LW, HSU YC, LEE TF, et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells[J]. BMC Gastroenterol, 2015, 15: 22. DOI: 10.1186/s12876-015-0248-8.
[21]	ELBASET MA, MOHAMED BMSA, HESSIN A, et al. Nrf2/HO-1, NF-κB and PI3K/Akt signalling pathways decipher the therapeutic mechanism of pitavastatin in early phase liver fibrosis in rats[J]. J Cell Mol Med, 2024, 28( 3): e18116. DOI: 10.1111/jcmm.18116.
[22]	IOANNOU GN, VAN ROOYEN DM, SAVARD C, et al. Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH[J]. J Lipid Res, 2015, 56( 2): 277- 285. DOI: 10.1194/jlr.M053785.
[23]	MEIRELES CZ, PASARIN M, LOZANO JJ, et al. Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation[J]. Shock, 2017, 47( 3): 370- 377. DOI: 10.1097/SHK.0000000000000734.
[24]	RELJA B, LEHNERT M, SEYBOTH K, et al. Simvastatin reduces mortality and hepatic injury after hemorrhage/resuscitation in rats[J]. Shock, 2010, 34( 1): 46- 54. DOI: 10.1097/SHK.0b013e3181cd8d05.
[25]	MURA VL, PASARÍN M, MEIRELES CZ, et al. Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction[J]. Hepatology, 2013, 57( 3): 1172- 1181. DOI: 10.1002/hep.26127.
[26]	LI YR, WANG M, HE FL, et al. Etiological and non-etiological therapies for cirrhotic portal hypertension[J]. J Clin Hepatol, 2022, 38( 6): 1224- 1228. DOI: 10.3969/j.issn.1001-5256.2022.06.003. 李悦榕, 王民, 何福亮, 等. 肝硬化门静脉高压的病因和非病因治疗[J]. 临床肝胆病杂志, 2022, 38( 6): 1224- 1228. DOI: 10.3969/j.issn.1001-5256.2022.06.003.
[27]	HIDE D, GIL M, ANDRADE F, et al. Simvastatin-loaded polymeric micelles are more effective and less toxic than conventional statins in a pre-clinical model of advanced chronic liver disease[J]. Nanomed-Nanotechnol Biol Med, 2020, 29: 102267. DOI: 10.1016/j.nano.2020.102267.
[28]	SCHIERWAGEN R, MAYBÜCHEN L, HITTATIYA K, et al. Statins improve NASH via inhibition of RhoA and Ras[J]. Am J Physiol Gastrointest Liver Physiol, 2016, 311( 4): G724- G733. DOI: 10.1152/ajpgi.00063.2016.
[29]	TRIPATHI DM, VILASECA M, LAFOZ E, et al. Simvastatin prevents progression of acute on chronic liver failure in rats with cirrhosis and portal hypertension[J]. Gastroenterology, 2018, 155( 5): 1564- 1577. DOI: 10.1053/j.gastro.2018.07.022.
[30]	LI LZ, ZHAO ZM, ZHANG L, et al. Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway[J]. J Appl Toxicol, 2019, 39( 10): 1394- 1404. DOI: 10.1002/jat.3825.
[31]	BENHAMMOU JN, QIAO B, KO A, et al. Lipophilic statins inhibit YAP coactivator transcriptional activity in HCC cells through Rho-mediated modulation of actin cytoskeleton[J]. Am J Physiol Gastrointest Liver Physiol, 2023, 325( 3): G239- G250. DOI: 10.1152/ajpgi.00089.2023.
[32]	RIDRUEJO E, ROMERO-CAÍMI G, OBREGÓN MJ, et al. Potential molecular targets of statins in the prevention of hepatocarcinogenesis[J]. Ann Hepatol, 2018, 17( 3): 490- 500. DOI: 10.5604/01.3001.0011.7394.
[33]	LIU PC, LU G, DENG Y, et al. Inhibition of NF-κB pathway and modulation of MAPK signaling pathways in glioblastoma and implications for lovastatin and tumor necrosis factor-related apoptosis inducing ligand(TRAIL) combination therapy[J]. PLoS One, 2017, 12( 1): e0171157. DOI: 10.1371/journal.pone.0171157.
[34]	GHALALI A, MARTIN-RENEDO J, HÖGBERG J, et al. Atorvastatin decreases HBx-induced phospho-akt in hepatocytes via P2X receptors[J]. Mol Cancer Res, 2017, 15( 6): 714- 722. DOI: 10.1158/1541-7786.MCR-16-0373.
[35]	D’SOUZA S, LAU KC, COFFIN CS, et al. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma[J]. World J Gastroenterol, 2020, 26( 38): 5759- 5783. DOI: 10.3748/wjg.v26.i38.5759.
[36]	FRANCIS P, FORMAN LM. Statins show promise against progression of liver disease[J]. Clin Liver Dis, 2021, 18( 6): 280- 287. DOI: 10.1002/cld.1143.
[37]	FENG J, DAI WQ, MAO YQ, et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis[J]. J Exp Clin Cancer Res, 2020, 39( 1): 24. DOI: 10.1186/s13046-020-1528-x.
[38]	KIM GW, IMAM H, KHAN M, et al. HBV-induced increased N6 methyladenosine modification of PTEN RNA affects innate immunity and contributes to HCC[J]. Hepatology, 2021, 73( 2): 533- 547. DOI: 10.1002/hep.31313.
[39]	IVANOV AV, VALUEV-ELLISTON VT, TYURINA DA, et al. Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis[J]. Oncotarget, 2017, 8( 3): 3895- 3932. DOI: 10.18632/oncotarget.13904.
[40]	KIM MH, KIM MY, SALLOUM S, et al. Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature[J]. Hepatol Commun, 2022, 6( 9): 2581- 2593. DOI: 10.1002/hep4.1991.
[41]	YANG YH, CHEN WC, TSAN YT, et al. Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection[J]. J Hepatol, 2015, 63( 5): 1111- 1117. DOI: 10.1016/j.jhep.2015.07.006.
[42]	LIANG YJ, SUN CP, HSU YC, et al. Statin inhibits large hepatitis delta antigen-Smad3-twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion[J]. J Biomed Sci, 2020, 27( 1): 65. DOI: 10.1186/s12929-020-00659-6.
[43]	FATIMA K, MOEED A, WAQAR E, et al. Efficacy of statins in treatment and development of non-alcoholic fatty liver disease and steatohepatitis: A systematic review and meta-analysis[J]. Clin Res Hepatol Gastroenterol, 2022, 46( 4): 101816. DOI: 10.1016/j.clinre.2021.101816.
[44]	VELL MS, LOOMBA R, KRISHNAN A, et al. Association of statin use with risk of liver disease, hepatocellular carcinoma, and liver-related mortality[J]. JAMA Netw Open, 2023, 6( 6): e2320222. DOI: 10.1001/jamanetworkopen.2023.20222.
[45]	WONG YJ, QIU TY, NG GK, et al. Efficacy and safety of statin for hepatocellular carcinoma prevention among chronic liver disease patients: A systematic review and meta-analysis[J]. J Clin Gastroenterol, 2021, 55( 7): 615- 623. DOI: 10.1097/MCG.0000000000001478.
[46]	MEURER L, COHEN SM. Drug-induced liver injury from statins[J]. Clin Liver Dis, 2020, 24( 1): 107- 119. DOI: 10.1016/j.cld.2019.09.007.
[47]	BENES LB, BASSI NS, DAVIDSON MH. The risk of hepatotoxicity, new onset diabetes and rhabdomyolysis in the era of high-intensity statin therapy: Does statin type matter?[J]. Prog Cardiovasc Dis, 2016, 59( 2): 145- 152. DOI: 10.1016/j.pcad.2016.08.001.