槲皮素对大鼠非酒精性脂肪肝炎的治疗作用及其机制
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摘要
目的观察槲皮素对大鼠非酒精性脂肪肝炎(NASH)的治疗作用,以及槲皮素对NASH大鼠肝组织核因子-κB(NF-κB)及其下游转录因子表达水平的影响。方法采用高脂饲料喂食6周,建立NASH大鼠模型。灌胃给予40~160 mg/kg槲皮素治疗4周。采用生化检测仪检测血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)水平。采用Western blotting法检测各组肝脏中NF-κB蛋白表达情况。采用RT-PCR技术检测各组肝脏中肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)和白细胞介素1β(IL-1β)mRNA的表达情况。结果与高脂模型组相比,槲皮素各剂量组大鼠血清LDL-C、TC、AST水平显著降低。病理组织学检查结果表明,给予槲皮素治疗后,可明显减轻NASH大鼠肝脏脂肪变性和炎性细胞浸润;同时,还可明显降低TNF-α、IL-6和IL-1β mRNA以及NF-κB p65蛋白的表达,并呈一定的量效关系。结论槲皮素对高脂饮食诱导大鼠NASH有明显治疗作用,作用机制可能与其抑制肝细胞脂质沉积和调控NF-κB通路有关。
Objective To investigate the therapeutic effects of quercetin on non-alcoholic steatohepatitis(NASH) in rats,and the effects of quercetin on expressions of nuclear factor-κB(NF-κB).Methods The rats were fed with a high-fat diet for 6 weeks to induce NASH.The NASH model rats were given by gavage with quercetin 40-160 mg/kg for 4 weeks.The levels of serum total cholesterol(TC),triglycerides(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),alanine aminotransferase(ALT),and aspartate aminotransferase(AST) were measured by the automatic blood chemical analyzer.The protein expressions of NF-κB in the hepatic tissues were detected by western blotting while tumor necrosis factor-α(TNF-α),interleukin-6(IL-6) and interleukin-1β(IL-1β)mRNA by RT-PCR.Results Compared with control groups,the serum levels of LDL-C,TC and AST were decreased significantly in the quercetin-treated groups.Oral administration of quercetin improved hepatic steatosis and inflammatory cell infiltration effectively in NASH rats,reduced the mRNA expressions of TNF-α,IL-6 and IL-1β,and down-regulated the protein expression of NF-κB,with a dose-dependent trend which can be observed.Conclusion Quercetin had significant therapeutic benefits to prevent NASH through inhibiting hepatic lipid accumulation,that may be works through regulating NF-κB pathway.
Objective To investigate the therapeutic effects of quercetin on non-alcoholic steatohepatitis(NASH) in rats,and the effects of quercetin on expressions of nuclear factor-κB(NF-κB).Methods The rats were fed with a high-fat diet for 6 weeks to induce NASH.The NASH model rats were given by gavage with quercetin 40-160 mg/kg for 4 weeks.The levels of serum total cholesterol(TC),triglycerides(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),alanine aminotransferase(ALT),and aspartate aminotransferase(AST) were measured by the automatic blood chemical analyzer.The protein expressions of NF-κB in the hepatic tissues were detected by western blotting while tumor necrosis factor-α(TNF-α),interleukin-6(IL-6) and interleukin-1β(IL-1β)mRNA by RT-PCR.Results Compared with control groups,the serum levels of LDL-C,TC and AST were decreased significantly in the quercetin-treated groups.Oral administration of quercetin improved hepatic steatosis and inflammatory cell infiltration effectively in NASH rats,reduced the mRNA expressions of TNF-α,IL-6 and IL-1β,and down-regulated the protein expression of NF-κB,with a dose-dependent trend which can be observed.Conclusion Quercetin had significant therapeutic benefits to prevent NASH through inhibiting hepatic lipid accumulation,that may be works through regulating NF-κB pathway.
引文
[1]Carr RM,Oranu A,Khungar V.Nonalcoholic fatty liver disease:pathophysiology and management[J].Gastroenterol Clin North Am,2016,45(4):639-652.
[2]Karim MF,Al-Mahtab M,Rahman S,et al.Non-alcoholic fatty liver disease(NAFLD)-a review[J].Mymensingh Med J,2015,24(4):873-880.
[3]郎雪楠,陈雪婷,董婉维,等.芹菜山楂汁对非酒精性脂肪肝模型小鼠血压、血脂、脂肪肝形成的影响[J].实验动物与比较医学,2016,36(2):134-1 36
[4]韩然,杨丹.p38丝裂原活化蛋白激酶通路在非酒精性脂肪肝中的作用[J].中国医药导报,2014,11(36):166-168.
[5]Li Y,Yao J,Han C,et al.Quercetin,inflammation and immunity[J].Nutrients,2016,8(3):167.
[6]谢湖均,雷群芳,方文军.槲皮素抗氧化活性的密度泛函理论研究[J].化学学报,2010,68(15):1467-1472.
[7]邓炜,冯崇廉,聂钊源,等.疏肝消脂Ⅲ方胶囊对非酒精性脂肪性肝病大鼠肝组织过氧化物酶体增殖物激活受体γ及脂联素受体2表达的影响[J].中西医结合肝病杂志,2016,26(2):96-98.
[8]Ying HZ,Liu YH,Yu B,et al.Dietary quercetin ameliorates nonalcoholic steatohepatitis induced by a high-fat diet in gerbils[J].Food Chem Toxicol,2013,52(10):53-60.
[9]Storniolo A,Raciti M,Cucina A,et al.Quercetin affects Hsp70/IRE1αmediated protection from death induced by endoplasmic reticulum stress[J].Oxid Med Cell Longev,2015,2015:645157.
[10]邓丽丽,臧家娜,应华忠,等.热休克蛋白70在兔非酒精性脂肪肝纤维化过程中的作用[J].实验动物与比较医学,2014,34(2):107-112.
[11]Kee JY,Han YH,Kim DS,et al.Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis,and suppression of metastatic ability[J].Phytomedicine,2016,23(13):1680-1690.
[12]Suganthy N,Devi KP,Nabavi SF,et al.Bioactive effects of quercetin in the central nervous system:focusing on the mechanisms of actions[J].Biomed Pharmacother,2016,84:892-908.
[13]Bhaskar S,Sudhakaran PR,Helen A,et al.Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-kB signaling pathway[J].Cell Immunol,2016,310:131-140.
[14]Porras D,Nistal E,Martinez-Florez S,et al.Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation[J].Free Radic Biol Med,2016,102:188-202.
[15]Liu L,Gao C,Yao P,et al.Quercetin alleviates high-fat dietinduced oxidized low-density lipoprotein accumulation in the liver:implication for autophagy regulation[J].Biomed Res Int,2015,2015:607531.
[16]Mohan SK,Veeraraghavan VP,Jainu M.Effect of pioglitazone,quercetin and hydroxy citric acid on extracellular matrix components in experimentally induced non-alcoholic steatohepatitis[J].Iran J Basic Med Sci,2015,18(8):832-836.
[17]Sharifnia T,Antoun J,Verriere TG,et al.Hepatic TLR4signaling in obese NAFLD[J].Am J Physiol Gastrointest Liver Physiol,2015,309(4):G270-G278.
[18]Michelotti GA,Machado MV,Diehl AM.NAFLD,NASH and liver cancer[J].Nat Rev Gastroenterol Hepatol,2013,10(ll):656-665.
[19]Chu-Sook Kim,Yoonhee Kwon,Suck-Young Choe,et al.Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1[J].Nutr Metab,2015,12:33.
[20]Surapaneni KM,Vishnu PV,Mallika J,et al.Effect of pioglitazone,quercetin,and hydroxy citric acid on vascular endothelial growth factor messenger RNA(VEGF mRNA)expression in experimentally induced nonalcoholic steatohepatitis(NASH)[J],Turk J Med Sci,2015,45(3):542-546.
[2]Karim MF,Al-Mahtab M,Rahman S,et al.Non-alcoholic fatty liver disease(NAFLD)-a review[J].Mymensingh Med J,2015,24(4):873-880.
[3]郎雪楠,陈雪婷,董婉维,等.芹菜山楂汁对非酒精性脂肪肝模型小鼠血压、血脂、脂肪肝形成的影响[J].实验动物与比较医学,2016,36(2):134-1 36
[4]韩然,杨丹.p38丝裂原活化蛋白激酶通路在非酒精性脂肪肝中的作用[J].中国医药导报,2014,11(36):166-168.
[5]Li Y,Yao J,Han C,et al.Quercetin,inflammation and immunity[J].Nutrients,2016,8(3):167.
[6]谢湖均,雷群芳,方文军.槲皮素抗氧化活性的密度泛函理论研究[J].化学学报,2010,68(15):1467-1472.
[7]邓炜,冯崇廉,聂钊源,等.疏肝消脂Ⅲ方胶囊对非酒精性脂肪性肝病大鼠肝组织过氧化物酶体增殖物激活受体γ及脂联素受体2表达的影响[J].中西医结合肝病杂志,2016,26(2):96-98.
[8]Ying HZ,Liu YH,Yu B,et al.Dietary quercetin ameliorates nonalcoholic steatohepatitis induced by a high-fat diet in gerbils[J].Food Chem Toxicol,2013,52(10):53-60.
[9]Storniolo A,Raciti M,Cucina A,et al.Quercetin affects Hsp70/IRE1αmediated protection from death induced by endoplasmic reticulum stress[J].Oxid Med Cell Longev,2015,2015:645157.
[10]邓丽丽,臧家娜,应华忠,等.热休克蛋白70在兔非酒精性脂肪肝纤维化过程中的作用[J].实验动物与比较医学,2014,34(2):107-112.
[11]Kee JY,Han YH,Kim DS,et al.Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis,and suppression of metastatic ability[J].Phytomedicine,2016,23(13):1680-1690.
[12]Suganthy N,Devi KP,Nabavi SF,et al.Bioactive effects of quercetin in the central nervous system:focusing on the mechanisms of actions[J].Biomed Pharmacother,2016,84:892-908.
[13]Bhaskar S,Sudhakaran PR,Helen A,et al.Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-kB signaling pathway[J].Cell Immunol,2016,310:131-140.
[14]Porras D,Nistal E,Martinez-Florez S,et al.Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation[J].Free Radic Biol Med,2016,102:188-202.
[15]Liu L,Gao C,Yao P,et al.Quercetin alleviates high-fat dietinduced oxidized low-density lipoprotein accumulation in the liver:implication for autophagy regulation[J].Biomed Res Int,2015,2015:607531.
[16]Mohan SK,Veeraraghavan VP,Jainu M.Effect of pioglitazone,quercetin and hydroxy citric acid on extracellular matrix components in experimentally induced non-alcoholic steatohepatitis[J].Iran J Basic Med Sci,2015,18(8):832-836.
[17]Sharifnia T,Antoun J,Verriere TG,et al.Hepatic TLR4signaling in obese NAFLD[J].Am J Physiol Gastrointest Liver Physiol,2015,309(4):G270-G278.
[18]Michelotti GA,Machado MV,Diehl AM.NAFLD,NASH and liver cancer[J].Nat Rev Gastroenterol Hepatol,2013,10(ll):656-665.
[19]Chu-Sook Kim,Yoonhee Kwon,Suck-Young Choe,et al.Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1[J].Nutr Metab,2015,12:33.
[20]Surapaneni KM,Vishnu PV,Mallika J,et al.Effect of pioglitazone,quercetin,and hydroxy citric acid on vascular endothelial growth factor messenger RNA(VEGF mRNA)expression in experimentally induced nonalcoholic steatohepatitis(NASH)[J],Turk J Med Sci,2015,45(3):542-546.