高血糖对非酒精性脂肪性肝炎大鼠肝纤维化形成的影响及机制探讨  

Effects of Hyperglycemia on the Hepatic Fibrogenesis in Non-Alcoholic Steatohepatitis Rats

作　　者：项标[1] 杜卫东[1] 夏超[1] 陈士明[1] 

机构地区：[1]浙江中医药大学附属第一医院肝胆外科,杭州310006

出　　处：《浙江中西医结合杂志》2016年第5期425-429,F0004,共6页Zhejiang Journal of Integrated Traditional Chinese and Western Medicine

基　　金：浙江省自然科学基金(No.Y2100826)

摘　　要：目的探讨高血糖对非酒精性脂肪性肝炎(NASH)大鼠肝纤维化形成的影响及机制。方法将60只SD大鼠随机数字法分成正常对照组、高血糖模型组、高血糖伴NASH组、氨基胍组和虎杖组,分别检测各组大鼠血糖值,病理学变化(HE染色),纤维化程度,肝组织基质金属蛋白酶组织抑制因子-1(TIMP-1)、转化生长因子-β1(TGF-β1)和晚期糖基化终产物(AGEs)含量的变化及各组大鼠α-平滑肌动蛋白(α-SMA)、结蛋白(desmin)的表达评分。结果 (1)血糖:氨基胍组和虎杖组大鼠血糖[(14.20±11.74)/(5.25±0.92)mmol/L]低于高血糖组[(22.20±1.70)mmol/L]和NASH组[(22.21±5.49)mmol/L](均P<0.05);(2)病理学改变:与正常对照组比较,高血糖组和NASH组肝组织出现细胞变性和纤维化改变。与NASH组比较,虎杖组肝细胞结构形态较正常,只有较轻度水肿、脂肪变性等炎性改变,未见明显纤维化;α-SMA[(4.92±1.69)分]、Desmin[(4.75±1.75)分]表达及TIMP-1[(3473.76±372.06)pg/m L]、TGF-β1[(125.26±28.60)ng/m L]、AGEs[(75.86±22.36)ng/m L]含量也显著降低(均P<0.01)。氨基胍组肝组织脂肪变性、水样变性、纤维化程度有所减轻,α-SMA表达增高(9.00±2.04)分(P<0.05),TIMP-1[(3543.67±377.05)pg/m L]、AGEs[(75.86±22.35)ng/m L]含量降低(P均<0.01),同时TGF-β1表达减低[(145.31±43.14)ng/m L],但差异无统计学意义(P>0.05)。结论高血糖可促进NASH大鼠肝纤维化形成,降低血糖和减少AGEs形成可减轻或抑制肝纤维化的发生;作用机制之一是激活肝星状细胞。虎杖较氨基胍改善NASH大鼠肝纤维化的作用更明显。Objective To investigate the effects of hyperglycemia on hepatic fibrogenesis in nonalcoholic steatohepatitis（NASH） mice and theunderlying mechanism. Methods Sixty SD rats were randomly divided into normal control group（n=10）, hyperglycemia group（n=12）, NASH group（n=14）, aminoguanidine group（n=12） and giant knotweed group（n=12）. Rats were induced by streptozotocin（STZ） to establish copied hyperglycemiamodel, then were treated with the corresponding drugs for glucose-loweringintervention. Rats were sacrificed to observe the degree of hepatic steatosis, inflammation, necrosis and fibrosis of liver tissue with HE staining. The expression of α-SMA and desmin in liver tissues was determined by immunohistochemistry, The fibrosis-relevant factorslike tissue inhibitor of metalloproteinase-1（TIMP-1）, transform growth factor β1（TGF-β1）, advanced glycation end products（AGEs） were assayed. Results The blood glucose in aminoguanidine and giant knotweed groups（14.20±11.74/5.25 ±0.92, mmol/L） was lower than that in hyperglycemia group（22.20 ±1.70mmol/L） and NASH group（22.21 ±5.49mmol/L）（all P〈0.05）. Lives tissue from hyperglycemia group and NASH group showed cell degeneration and fibrogenesis, while the hepatic tissue in giant knotweed groupdisplayed a normal form, mild edema and fatty degeneration and inflammatory cell infiltration and markedly alleviatedhepatic fibrosis, and reduced α-SMA（4.92±1.69）,desmin（4.75±1.75）, TIMP-1（3473.76±372.06pg/m L）, TGF-β1（125.26±28.60ng/m L）, and AGEs（75.86±22.36pg/m L）（all P〈0.01）. The pathology of hepatic tissue in aminoguanidine group was not improved significantly, but the fatty degeneration, hydropic degeneration, and hepatic fibrosis were slightly alleviated, and TIMP-1（3543.67 ±377.05pg/m L） and AGEs（75.86±22.35pg/m L） declined in content（P〈0.01）, α-SMA（9.00±2.04） increased（P〈0.05）, and TGF-β1（145.3±43.14ng/m L） reduced without statistical difference（P〈

关 键 词：大鼠 高血糖 非酒精性脂肪性肝炎 肝纤维化 虎杖 氨基胍 

分 类 号：R587.1[医药卫生—内分泌] R575.1[医药卫生—内科学]