天然药物对非酒精性脂肪肝的作用
|
摘要
非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)是世界上最常见的慢性肝病,是由环境、遗传背景以及代谢应激之间相互作用产生的多因素疾病。所涉及到的机制复杂,目前已经证实的治疗NAFLD最有效的方法是,饮食干预和锻炼以减轻体重,尚未有专门用于治疗NAFLD的药物。大量的体内外实验证实,多种天然药物可以通过各种机制来干预NAFLD,且疗效显著。本文主要总结了近年来常用天然药物防治NAFLD的研究进展,为进一步的新药研发提供信息。
Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in the world.It is a multifactorial disease caused by the interaction of environment, genetic background and metabolic stress. The mechanisms involved are complex and it has been demonstrated that the most effective treatment for NAFLD is diet intervention and exercise to lose weight. There are no drugs specifically designed to treat NAFLD. Many in vitro and in vivo tests have confirmed that a variety of natural medicines can intervene in NAFLD through various mechanisms, and the curative effect is remarkable. This paper mainly summarizes the research progress of natural medicines in prevention and treatment of NAFLD in recent years, and provides information for further research and development of new drugs.
Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in the world.It is a multifactorial disease caused by the interaction of environment, genetic background and metabolic stress. The mechanisms involved are complex and it has been demonstrated that the most effective treatment for NAFLD is diet intervention and exercise to lose weight. There are no drugs specifically designed to treat NAFLD. Many in vitro and in vivo tests have confirmed that a variety of natural medicines can intervene in NAFLD through various mechanisms, and the curative effect is remarkable. This paper mainly summarizes the research progress of natural medicines in prevention and treatment of NAFLD in recent years, and provides information for further research and development of new drugs.
引文
[1]BellentaniS. Theepidemiologyofnon-alcoholicfatty liver disease. Liver Int, 2017, 37 Suppl 1:81-84
[2]Fang YL,ChenH,WangCL,etal.Pathogenesisof non-alcoholic fatty liver disease in children and adolescence:From“twohittheory”to“multiplehitmodel”.World J Gastroenterol, 2018, 24(27):2974-2983
[3]Italian AssociationfortheStudyoftheLiver(AISF).AISF position paper on nonalcoholic fatty liver disease(NAFLD):Updates and future directions. Dig Liver Dis,2017, 49(5):471-483
[4]TiniakosDG, VosMB,BruntEM.Nonalcoholicfatty liverdisease:pathologyandpathogenesis. AnnuRev Pathol, 2010, 5:145-171
[5]Derra A, Bator M, Men?yk T, et al. Underrated enemy–from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract. Clin Exp Hepatol, 2018, 4(2):55-71
[6]Hannah WJ,HarrisonSA.Lifestyleanddietaryinterventions in the management of nonalcoholic fatty liver disease. Dig Dis Sci, 2016, 61(5):1365-1374
[7]Chiu TH, Lin MN, Pan WH, et al. Vegetarian diet, food substitution, and nonalcoholic fatty liver. Ci Ji Yi Xue Za Zhi, 2018, 30(2):102-109
[8]HaukelandJW,KonopskiZ,EggesboHB,etal.Metformin in patients with non-alcoholic fatty liver disease:arandomized,controlledtrial.ScandJGastroenterol,2009, 44(7):853-860
[9]European Association for the Study of the Liver(EASL),European Association for the Study of Diabetes(EASD),European Association for the Study of Obesity(EASO).EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol, 2016, 64(6):1388-1402
[10]Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis andmanagementofnon-alcoholicfattyliverdisease:practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases,and AmericanCollegeofGastroenterology.Gastroenterology, 2012, 142(7):1592-1609
[11]IpsenDH,LykkesfeldtJ, Tveden-NyborgP.Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci, 2018, 75(18):3313-3327
[12]Rodriguez-RamiroI, VauzourD,Minihane AM.Polyphenols and non-alcoholic fatty liver disease:impact and mechanisms. Proc Nutr Soc, 2016, 75(1):47-60
[13]He W, Xu Y, Zhang C, et al. Hepatoprotective effect of calculus bovis sativus on nonalcoholic fatty liver disease inmicebyinhibitingoxidativestressandapoptosisof hepatocytes. Drug Des Devel Ther, 2017, 11:3449-3460
[14]Hong M, Cai Z, Song L, et al. Gynostemma pentaphyllum attenuates the progression of nonalcoholic fatty liver diseaseinmice:abiomedicalinvestigationintegrated withinsilicoassay.EvidBasedComplement Alternat Med, 2018, doi:10.1155/2018/8384631
[15]Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Dig Dis, 2010, 28(1):179-185
[16]Zhang DD, Zhang JG, Wu X, et al. Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells. Front Pharmacol,2015, 6:238
[17]Hong M, Lee Y H, Kim S, et al. Anti-inflammatory and antifatigue effect of Korean Red Ginseng in patients with nonalcoholicfattyliverdisease.JGinsengRes,2016,40(3):203-210
[18]Lai YS, Lee WC, Lin YE, et al. Ginger essential oil ameliorateshepaticinjuryandlipidaccumulationinhigh fat diet-induced nonalcoholic fatty liver disease. J Agric Food Chem, 2016, 64(10):2062-2071
[19]Ahmed MH, Byrne CD. Modulation of sterol regulatory elementbindingproteins(SREBPs)aspotentialtreatmentsfornon-alcoholicfattyliverdisease(NAFLD).Drug Discov Today, 2007, 12(17-18):740-747
[20]Wang C, Li Y, Hao M, et al. Astragaloside IV inhibits triglyceride accumulation in insulin-resistant HepG2 cells via AMPK-inducedSREBP-1cphosphorylation.Front Pharmacol, 2018, 9:345
[21]Seo MS, Kim JH, Kim HJ, et al. Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulationinhepatocytes. Toxicol ApplPharmacol,2015, 284(2):113-124
[22]Li W,Li Y, WangQ,etal.CrudeextractsfromLyciumbarbarumsuppressSREBP-1cexpressionandpreventdiet-inducedfattyliverthrough AMPKactivation.Biomed Res Int, 2014, doi:10.1155/2014/196198
[23]Jia Y, WuC,KimJ,etal. Astaxanthinreduceshepatic lipidaccumulationsinhigh-fat-fedC57BL/6Jmicevia activation of peroxisome proliferator-activated receptor(PPAR)alpha and inhibition of PPAR gamma and Akt. J Nutr Biochem, 2016, 28:9-18
[24]Ann JY, Eo H, Lim Y. Mulberry leaves(Morus alba L.)ameliorate obesity-induced hepatic lipogenesis, fibrosis,andoxidativestressinhigh-fatdiet-fedmice.Genes Nutr, 2015, 10(6):46
[25]LouZ,XiaB,SuJ,etal.Effectofastilbeneglycoside-richextractfromPolygoniMultifloriRadixon experimental non-alcoholic fatty liver disease based on principal component and orthogonal partial least squares discriminant analysis. Exp Ther Med, 2017, 14(5):4958-4966
[26]Lin P, He YR, Lu JM, et al. In vivo lipid regulation mechanismofpolygonimultifloriradixinhigh-fatdietfed rats. Evid Based Complement Alternat Med, 2014, doi:10.1155/2014/642058
[27]Wang T, An Y, Zhao C, et al. Regulation effects of Crataegus pinnatifida leaf on glucose and lipids metabolism.J Agric Food Chem, 2011, 59(9):4987-4994
[28]Li Z, Xu J, Zheng P, et al. Hawthorn leaf flavonoids alleviate nonalcoholic fatty liver disease by enhancing the adiponectin/AMPK pathway. Int J Clin Exp Med, 2015,8(10):17295-17307
[29]Su XZ, Miller LH. The discovery of artemisinin and the Nobel Prize in Physiology or Medicine. Sci China Life Sci, 2015, 58(11):1175-1179
[30]KimMH,SeoJY,LiuKH,etal.Protectiveeffectof Artemisia annua L. extract against galactose-induced oxidative stress in mice. PLoS One, 2014, 9(7):e101486
[31]Kim KE, Ko KH, Heo RW, et al. Artemisia annua leaf extract attenuates hepatic steatosis and inflammation in high-fat diet-fed mice. J Med Food, 2016, 19(3):290-299
[32]Shishodia S. Molecular mechanisms of curcumin action:gene expression. Biofactors, 2013, 39(1):37-55
[33]Das L, Vinayak M. Long term effect of curcumin in restoration of tumour suppressor p53 and phase-II antioxidant enzymes via activation of Nrf2 signalling and modulationofinflammationinpreventionofcancer.PLoS One, 2015, 10(4):e0124000
[34]Shapiro H, Bruck R. Therapeutic potential of curcumin in non-alcoholic steatohepatitis. Nutr Res Rev, 2005, 18(2):212-221
[35]Inzaugarat ME, De Matteo E, Baz P, et al. New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans. PLoS One, 2017,12(3):e0172900
[36]Ahangarpour A,Oroojan A A,KhorsandiL,etal.Preventiveeffectsofbetulinicacidonstreptozotocinnicotinamide induced diabetic nephropathy in male mouse. J Nephropathol, 2016, 5(4):128-133
[37]Ahangarpour A, Shabani R, Farbood Y. The effect of betulinic acid on leptin, adiponectin, hepatic enzyme levels and lipid profiles in streptozotocin-nicotinamide-induced diabetic mice. Res Pharm Sci, 2018, 13(2):142-148
[38]Quan HY, Kim DY, Kim SJ, et al. Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway.Biochem Pharmacol, 2013, 85(9):1330-1340
[39]Neag MA, Mocan A, Echeverría J, et al. Berberine:botanical occurrence, traditional uses, extraction methods,and relevance in cardiovascular, metabolic, hepatic, and renal disorders. Front Pharmacol, 2018, 9:557
[40]Ma X, Chen Z, Wang L, et al. The pathogenesis of diabetes mellitus by oxidative stress and inflammation:its inhibition by berberine. Front Pharmacol, 2018, 9:782
[41]Zhang X, Zhao Y, Zhang M, et al. Structural changes of gut microbiota during berberine-mediated prevention of obesityandinsulinresistanceinhigh-fatdiet-fedrats.PLoS One, 2012, 7(8):e42529
[42]Li D, Zheng J, Hu Y, et al. Amelioration of intestinal barrier dysfunction by berberine in the treatment of nonalcoholic fatty liver disease in rats. Pharmacogn Mag, 2017,13(52):677-682
[43]YuanX, WangJ, TangX,etal.Berberineameliorates nonalcoholic fatty liver disease by a global modulation of hepatic mRNA and lncRNA expression profiles. J Transl Med, 2015, 13:24
[44]Zhang Y,ZhangZ, WangH,etal.NeuroprotectiveeffectofginsenosideRg1preventscognitiveimpairment induced by isoflurane anesthesia in aged rats via antioxidant,anti-inflammatoryandanti-apoptoticeffectsmediated by the PI3K/AKT/GSK-3beta pathway. Mol Med Rep, 2016, 14(3):2778-2784
[45]Gao Y,ChuS,ShaoQ,etal. Antioxidantactivitiesof ginsenoside Rg1 against cisplatin-induced hepatic injury throughNrf2signalingpathwayinmice.FreeRadical Research, 2017, 51(1):1-13
[46]徐雅姝,秦圆圆,黄文祥,等.人参皂苷Rg1对小鼠非酒精性脂肪肝的改善作用和机制研究.重庆医科大学学报, 2018, 10.13406/j.cnki.cyxb.001757
[2]Fang YL,ChenH,WangCL,etal.Pathogenesisof non-alcoholic fatty liver disease in children and adolescence:From“twohittheory”to“multiplehitmodel”.World J Gastroenterol, 2018, 24(27):2974-2983
[3]Italian AssociationfortheStudyoftheLiver(AISF).AISF position paper on nonalcoholic fatty liver disease(NAFLD):Updates and future directions. Dig Liver Dis,2017, 49(5):471-483
[4]TiniakosDG, VosMB,BruntEM.Nonalcoholicfatty liverdisease:pathologyandpathogenesis. AnnuRev Pathol, 2010, 5:145-171
[5]Derra A, Bator M, Men?yk T, et al. Underrated enemy–from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract. Clin Exp Hepatol, 2018, 4(2):55-71
[6]Hannah WJ,HarrisonSA.Lifestyleanddietaryinterventions in the management of nonalcoholic fatty liver disease. Dig Dis Sci, 2016, 61(5):1365-1374
[7]Chiu TH, Lin MN, Pan WH, et al. Vegetarian diet, food substitution, and nonalcoholic fatty liver. Ci Ji Yi Xue Za Zhi, 2018, 30(2):102-109
[8]HaukelandJW,KonopskiZ,EggesboHB,etal.Metformin in patients with non-alcoholic fatty liver disease:arandomized,controlledtrial.ScandJGastroenterol,2009, 44(7):853-860
[9]European Association for the Study of the Liver(EASL),European Association for the Study of Diabetes(EASD),European Association for the Study of Obesity(EASO).EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol, 2016, 64(6):1388-1402
[10]Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis andmanagementofnon-alcoholicfattyliverdisease:practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases,and AmericanCollegeofGastroenterology.Gastroenterology, 2012, 142(7):1592-1609
[11]IpsenDH,LykkesfeldtJ, Tveden-NyborgP.Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci, 2018, 75(18):3313-3327
[12]Rodriguez-RamiroI, VauzourD,Minihane AM.Polyphenols and non-alcoholic fatty liver disease:impact and mechanisms. Proc Nutr Soc, 2016, 75(1):47-60
[13]He W, Xu Y, Zhang C, et al. Hepatoprotective effect of calculus bovis sativus on nonalcoholic fatty liver disease inmicebyinhibitingoxidativestressandapoptosisof hepatocytes. Drug Des Devel Ther, 2017, 11:3449-3460
[14]Hong M, Cai Z, Song L, et al. Gynostemma pentaphyllum attenuates the progression of nonalcoholic fatty liver diseaseinmice:abiomedicalinvestigationintegrated withinsilicoassay.EvidBasedComplement Alternat Med, 2018, doi:10.1155/2018/8384631
[15]Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Dig Dis, 2010, 28(1):179-185
[16]Zhang DD, Zhang JG, Wu X, et al. Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells. Front Pharmacol,2015, 6:238
[17]Hong M, Lee Y H, Kim S, et al. Anti-inflammatory and antifatigue effect of Korean Red Ginseng in patients with nonalcoholicfattyliverdisease.JGinsengRes,2016,40(3):203-210
[18]Lai YS, Lee WC, Lin YE, et al. Ginger essential oil ameliorateshepaticinjuryandlipidaccumulationinhigh fat diet-induced nonalcoholic fatty liver disease. J Agric Food Chem, 2016, 64(10):2062-2071
[19]Ahmed MH, Byrne CD. Modulation of sterol regulatory elementbindingproteins(SREBPs)aspotentialtreatmentsfornon-alcoholicfattyliverdisease(NAFLD).Drug Discov Today, 2007, 12(17-18):740-747
[20]Wang C, Li Y, Hao M, et al. Astragaloside IV inhibits triglyceride accumulation in insulin-resistant HepG2 cells via AMPK-inducedSREBP-1cphosphorylation.Front Pharmacol, 2018, 9:345
[21]Seo MS, Kim JH, Kim HJ, et al. Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulationinhepatocytes. Toxicol ApplPharmacol,2015, 284(2):113-124
[22]Li W,Li Y, WangQ,etal.CrudeextractsfromLyciumbarbarumsuppressSREBP-1cexpressionandpreventdiet-inducedfattyliverthrough AMPKactivation.Biomed Res Int, 2014, doi:10.1155/2014/196198
[23]Jia Y, WuC,KimJ,etal. Astaxanthinreduceshepatic lipidaccumulationsinhigh-fat-fedC57BL/6Jmicevia activation of peroxisome proliferator-activated receptor(PPAR)alpha and inhibition of PPAR gamma and Akt. J Nutr Biochem, 2016, 28:9-18
[24]Ann JY, Eo H, Lim Y. Mulberry leaves(Morus alba L.)ameliorate obesity-induced hepatic lipogenesis, fibrosis,andoxidativestressinhigh-fatdiet-fedmice.Genes Nutr, 2015, 10(6):46
[25]LouZ,XiaB,SuJ,etal.Effectofastilbeneglycoside-richextractfromPolygoniMultifloriRadixon experimental non-alcoholic fatty liver disease based on principal component and orthogonal partial least squares discriminant analysis. Exp Ther Med, 2017, 14(5):4958-4966
[26]Lin P, He YR, Lu JM, et al. In vivo lipid regulation mechanismofpolygonimultifloriradixinhigh-fatdietfed rats. Evid Based Complement Alternat Med, 2014, doi:10.1155/2014/642058
[27]Wang T, An Y, Zhao C, et al. Regulation effects of Crataegus pinnatifida leaf on glucose and lipids metabolism.J Agric Food Chem, 2011, 59(9):4987-4994
[28]Li Z, Xu J, Zheng P, et al. Hawthorn leaf flavonoids alleviate nonalcoholic fatty liver disease by enhancing the adiponectin/AMPK pathway. Int J Clin Exp Med, 2015,8(10):17295-17307
[29]Su XZ, Miller LH. The discovery of artemisinin and the Nobel Prize in Physiology or Medicine. Sci China Life Sci, 2015, 58(11):1175-1179
[30]KimMH,SeoJY,LiuKH,etal.Protectiveeffectof Artemisia annua L. extract against galactose-induced oxidative stress in mice. PLoS One, 2014, 9(7):e101486
[31]Kim KE, Ko KH, Heo RW, et al. Artemisia annua leaf extract attenuates hepatic steatosis and inflammation in high-fat diet-fed mice. J Med Food, 2016, 19(3):290-299
[32]Shishodia S. Molecular mechanisms of curcumin action:gene expression. Biofactors, 2013, 39(1):37-55
[33]Das L, Vinayak M. Long term effect of curcumin in restoration of tumour suppressor p53 and phase-II antioxidant enzymes via activation of Nrf2 signalling and modulationofinflammationinpreventionofcancer.PLoS One, 2015, 10(4):e0124000
[34]Shapiro H, Bruck R. Therapeutic potential of curcumin in non-alcoholic steatohepatitis. Nutr Res Rev, 2005, 18(2):212-221
[35]Inzaugarat ME, De Matteo E, Baz P, et al. New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans. PLoS One, 2017,12(3):e0172900
[36]Ahangarpour A,Oroojan A A,KhorsandiL,etal.Preventiveeffectsofbetulinicacidonstreptozotocinnicotinamide induced diabetic nephropathy in male mouse. J Nephropathol, 2016, 5(4):128-133
[37]Ahangarpour A, Shabani R, Farbood Y. The effect of betulinic acid on leptin, adiponectin, hepatic enzyme levels and lipid profiles in streptozotocin-nicotinamide-induced diabetic mice. Res Pharm Sci, 2018, 13(2):142-148
[38]Quan HY, Kim DY, Kim SJ, et al. Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway.Biochem Pharmacol, 2013, 85(9):1330-1340
[39]Neag MA, Mocan A, Echeverría J, et al. Berberine:botanical occurrence, traditional uses, extraction methods,and relevance in cardiovascular, metabolic, hepatic, and renal disorders. Front Pharmacol, 2018, 9:557
[40]Ma X, Chen Z, Wang L, et al. The pathogenesis of diabetes mellitus by oxidative stress and inflammation:its inhibition by berberine. Front Pharmacol, 2018, 9:782
[41]Zhang X, Zhao Y, Zhang M, et al. Structural changes of gut microbiota during berberine-mediated prevention of obesityandinsulinresistanceinhigh-fatdiet-fedrats.PLoS One, 2012, 7(8):e42529
[42]Li D, Zheng J, Hu Y, et al. Amelioration of intestinal barrier dysfunction by berberine in the treatment of nonalcoholic fatty liver disease in rats. Pharmacogn Mag, 2017,13(52):677-682
[43]YuanX, WangJ, TangX,etal.Berberineameliorates nonalcoholic fatty liver disease by a global modulation of hepatic mRNA and lncRNA expression profiles. J Transl Med, 2015, 13:24
[44]Zhang Y,ZhangZ, WangH,etal.NeuroprotectiveeffectofginsenosideRg1preventscognitiveimpairment induced by isoflurane anesthesia in aged rats via antioxidant,anti-inflammatoryandanti-apoptoticeffectsmediated by the PI3K/AKT/GSK-3beta pathway. Mol Med Rep, 2016, 14(3):2778-2784
[45]Gao Y,ChuS,ShaoQ,etal. Antioxidantactivitiesof ginsenoside Rg1 against cisplatin-induced hepatic injury throughNrf2signalingpathwayinmice.FreeRadical Research, 2017, 51(1):1-13
[46]徐雅姝,秦圆圆,黄文祥,等.人参皂苷Rg1对小鼠非酒精性脂肪肝的改善作用和机制研究.重庆医科大学学报, 2018, 10.13406/j.cnki.cyxb.001757