目的 观察白芍总苷对果糖-高脂诱导非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)大鼠肝脏组织胞外信号调节激酶-1/2(p-ERK1/2)、Toll样受体-4(TLR4)和Toll样受体-9(TLR9)蛋白的表达。 方法 SD大鼠随机分为正常对照组和果糖-高脂诱导造模组,后者连续10周果糖-高脂喂饲;第6周末建立疾病模型后,病鼠随机分为模型组、二甲双胍组(200 mg·kg-1)、白芍总苷低剂量组(100 mg·kg-1)和高剂量组(200 mg·kg-1),每组均为10只。用药4周后处死所有实验大鼠,观察上述药物对血清空腹血糖(FBG),胰岛素含量(FIns),胰岛素敏感指数(ISI),胆固醇(TC),低密度脂蛋白-胆固醇(LDL-C),高密度脂蛋白-胆固醇(HDL-C),三酰甘油(TG),游离脂肪酸(FFA)含量,检测丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、谷胱甘肽转移酶(GST)活性和肝脏指数(liver index),以及采用蛋白质印迹法检测肝脏组织p-ERK1/2、Toll样受体-4、TLR9蛋白表达。 结果 与正常大鼠比较,模型大鼠血糖、胰岛素、胆固醇、低密度脂蛋白-胆固醇、三酰甘油及游离脂肪酸含量、丙氨酸氨基转移酶、天冬氨酸氨基转移酶和谷胱甘肽转移酶的活性单位、肝脏指数、p-ERK1/2、Toll样受体-4和TLR9蛋白表达明显上调(P＜0.01或P＜0.05),胰岛素敏感指数水平及高密度脂蛋白-胆固醇含量明显降低(P<0.01),二甲双胍和白芍总苷低、高剂量组均能改善此现象(P<0.01或P<0.05),但对丙氨酸氨基转移酶的含量改变没有统计学差异(P>0.05)。 结论 白芍总苷能改善果糖-高脂诱导非酒精性脂肪性肝病大鼠糖脂代谢异常及拮抗胰岛素抵抗,增强胰岛素敏感性,改善肝功能;其作用机制与白芍总苷下调肝脏组织p-ERK1/2、Toll样受体-4、TLR9蛋白表达作用有关。
Abstract
OBJECTIVE To investigate total glucosides paeony(TGP) on the expression phosphorylated extracellelar signal regulated kinase 1/2(p-ERK1/2), Toll-like receptors 4(TLR4) and Toll-like receptors 9(TLR9) in rats with nonalcoholic fatty liver disease(NAFLD) induced by fructose and high-fat feed. METHODS SD rats were divided into normal group and test groups. The rats in test groups were fed with fructose and high-fat feed for 10 weeks totally to induce the test model. After 6 weeks the model was established, the rats were divided into four groups randomly, the model group(NAFLD), the metformin group(Met, 200 mg穔g-1), the low-dose TGP group(TGP-L, 100 mg穔g-1) and the high-dose TGP group(TGP-H, 200 mg穔g-1)(n=10). Four weeks later all the rats were killed and checked the indexes such as serum fasting blood glucose(FBG), fasting insulin(FIns), insulin sensitivity index(ISI), total cholesterol(TC), low-density lipoprotein(LDL-C), high-density lipoprotein(HDL-C), triglyceride(TG), free fatty acids(FFA), alanine aminotransferase(ALT), aspartate aminotransferase(AST), glutathione S-transferase(GST) and liver index. The expression p-ERK1/2, TLR4 and TLR9 were inspected by Western-blot. RESULTS Compared with the normal group, the rats in test groups were with the high levels serum FBG, insulin, TC, LDL-C, TG, FFA, ALT, AST, GST, liver index, p-ERK1/2, TLR4 and TLR9 (P<0.01 or P<0.05), when the levels ISI and HDL-C were low(P<0.01). The Met, low-dose TGP and high-dose TGP worked on all the targets (P<0.01 or P<0.05) except the changes ALT (P>0.05). CONCLUSION By downregulating the expression ERK1/2, TLR4 and TRL9, TGP can improve abnormal glucose and lipid metabolism and insulin resistance, enhance insulin sensitivity and ameliorate liver function in rats with NAFLD induced by fructose and high-fat feed.
关键词
白芍总苷 /
果糖 /
非酒精性脂肪性肝病 /
胰岛素抵抗 /
二甲双胍 /
胞外信号调节激酶-1/2 /
Toll样受体-4 /
Toll样受体-9
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Key words
total glucosides paeony(TGP) /
fructose /
nonalcoholic fatty liver disease(NAFLD) /
insulin resistance(IR) /
metformin(Met) /
extracellular signal-regulated kinase-1/2(ERK1/2) /
Toll-like receptors -4(TLR4) /
Toll-like receptors -9(TLR9)
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中图分类号：
R965
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参考文献
[1] RAHIMI R S, LANDAVERDE C. Nonalcoholic fatty liver disease and the metabolic syndrome:Clinical implications and treatment. Nutr Clin Pract, 2013,28(1):40-51.[2] BASARANOGLU M, BASARANOGLU G, SABUNCU T, et al. Fructose as a key player in the development fatty liver disease. World J Gastroenterol, 2013,19(8):1166-1172. [3] DE CASTRO U G, DOS SANTOS R A, SILVA M E, et al. Age-dependent effect high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney rats. Lipids Health Dis, 2013,18(12):136.[4] ZHENG L Y, PAN J Q, L J H. Effects total glucosides paeony on enhancing insulin sensitivity and antagonizing nonalcoholic fatty liver in rats. China J Chin Mater Med(中国中药杂志), 2008,33(20):2385-2390.[5] ZHAO R X, ZHENG L Y, L J H, et al. The antioxidative mechanism total glucosides paeony on protection against the fatty liver in NAFLD rats. J Guangdong Pharm Univ(广东药学院学报), 2012,28(4):231-235.[6] ZHENG L Y, PAN J Q, YANG Y L, et al. Effect total glucosides paeony on apelin and visfatin expression in rats with nonalcoholic fatty liver disease. Tradit Chin Drug Res Clin Pharmacol(中药临床药理学), 2013,24(1):51-54.[7] HENAO-MEJIA J, ELINAV E, JIN C, et al. Inflammasome-mediated dysbiosis regulates progression NAFLD and obesity. Nature, 2012,482(7384):179-185[8] YOUL E, BARDY G, MAGOUS R, et al. Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway. Br J Pharmacol, 2010,161(4):799-814.[9] ZHANG W, WANG L W, WANG L K, et al. Betaine protects against high-fat-diet-induced liver injury by inhibition high-mobility group box 1 and Toll-like receptor 4 expression in rats. Dig Dis Sci, 2013,58(11):3198-3206. WU Z C , WANG H, YU H Y. The insulin signal path associated with cell proliferation. Chin J Gerontol(中国老年病学), 2009,15(29):1988-1990. QIN B, ANDERSON R A, ADELI K. Tumor necrosis factor-alpha directly stimulates the overproduction hepatic apolipoprotein B100-containing VLDL via impairment hepatic insulin signaling. Am J Physiol Gastrointest Liver Physiol, 2008,294(5):1120-1129. KLASCHIK S, GURSEL I, KLNMAND M. CpG-mediated changes in gene expression in murine spleen cells identified by microarray analysis. Mol Immunol, 2007,44(6):1095-1104. SPRUSS A, KANURI G, WAGNERBERGER S, et al. Toll-like receptor4 is involved in the development fructose-induced hepatic steatosis in mice. Hepatology, 2009,50(4):1004-1006. SHIRAI Y, YOSHIJI H, NOGUCHI R, et al. Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model non-alcoholic steatohepatitis. J Gastroenterol Hepatol, 2013, 28(4):723-730.
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脚注
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基金
广州市科技计划项目(2010Y1-C491);广州市中医药中西医结合科技项目(2009-A-10)
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