目的 观察替米沙坦通过激活过氧化物酶体增殖因子活化受体γ(PPAR γ)对非酒精性脂肪性肝炎大鼠的保护作用.方法 将30只雄性SD大鼠随机分为对照组、模型组和干预组,每组10只.模型组和干预组给予高脂饲料喂养16周诱发脂肪性肝炎,其中干预组于高脂喂养12周后,给予替米沙坦(5 mg·kg-1·d-1)灌胃治疗4周.16周末处死大鼠,分别进行如下检测:(1)光学显微镜下观察肝脏病理变化;(2)检测血清ALT、AST、空腹胰岛素(FINS)、空腹血糖(FBG)、肿瘤坏死因子α(TNF α)和脂联素水平,计算稳态模型的胰岛素抵抗指数(HOMA-IR);(3)用半定量逆转录-聚合酶链反应和Western blot检测肝组织过氧化物酶体增殖物激活受体γ(PPAR γ)mRNA和蛋白的表达水平.用SPSS 13.0统计软件处理,计量资料以均数±标准差(x-±s)表示,多组间比较用单因素方差分析,组间比较用Student-Newman-Keuls q检验,等级资料组间比较用秩和检验,脂联素、TNF α与HOMA-IR的关联性用直线相关分析.结果 (1)模型组大鼠造模均成功,根据肝细胞脂肪变性占所获肝组织标本量的范围分为4度(F0～4),其中模型组大鼠肝细胞脂肪变程度达F3、F4的分别有1、9只.干预组脂肪变性程度达F1、F2、F3的大鼠分别有1、6、3只.对照组大鼠肝组织炎症活动度积分为0.模型组大鼠肝组织炎症活动度积分为2.67±0.27,与对照组比较,U=15,P＜0.01,差异有统计学意义.干预组炎症活动度积分为1.36±0.12,与模型组比较,U=24,P＜0.05,差异有统计学意义.(2)对照组ALT、AST、FBG、FINS、HOMA-IR、TNF α分别为(48.20±10.99)U/L、(153.00±45.06)U/L、(4.58±1.00)mmol/L、(10.48±1.46)μU/ml、2.13±0.29、(1.38±0.75)μg/L,模型组分别为(114.00±19.7)U/L、(265.33±52.10)U/L、(6.58±0.86)mmoL/L、(20.73±0.91)μ U/ml、6.23±0.10、(3.47±0.19)μg/L,干预组分别为(78.80±15.64)U/L、(211.83±65.51)U/L、(5.38±0.88)mmol/L、(15.02±1.22)μU/ml、3.59±0.29、(1.58±0.13)μg/L,与对照组比较,模型组血清ALT、AST、FINS、FBG、HOMA-IR、TNF α升高,q值分别为13.130、6.472、6.909、26.619、49.683、14.591,P值均＜0.01,差异有统计学意义.与模型组比较,干预组血清ALT、FINS、FBG、HOMA-IR、TNFα降低,q值分别为7.024、4.145、14.829、31.991、13.195,P值均＜0.01,差异有统计学意义.(3)对照组血清脂联素、肝组织PPARγ mRNA和蛋白的表达分别为(8.93±0.44)mg/L、1.19±0.35、0.93±0.44,干预组分别为(7.12±1.00)mg/L、0.79±0.15、0.58±1.00,模型组分别为(6.09±0.96)mg/L、0.57±0.09、0.36±0.96.对照组与模型组比较,q值分别为10.696、8.679、16.762,P值均＜0.05,差异均有统计学意义;干预组与模型组比较,q值分别为3.879、3.079、6.400,P值均＜0.05,差异均有统计学意义.相关分析显示,脂联素水平与HOMA-IR呈负相关(r=-0.891,P＜0.01),TNFα水平与HOMA-IR呈正相关(r=0.927,P＜0.01).结论 替米沙坦可能通过促进PPARγ的表达对NASH大鼠产生保护作用.
目的 觀察替米沙坦通過激活過氧化物酶體增殖因子活化受體γ(PPAR γ)對非酒精性脂肪性肝炎大鼠的保護作用.方法 將30隻雄性SD大鼠隨機分為對照組、模型組和榦預組,每組10隻.模型組和榦預組給予高脂飼料餵養16週誘髮脂肪性肝炎,其中榦預組于高脂餵養12週後,給予替米沙坦(5 mg·kg-1·d-1)灌胃治療4週.16週末處死大鼠,分彆進行如下檢測:(1)光學顯微鏡下觀察肝髒病理變化;(2)檢測血清ALT、AST、空腹胰島素(FINS)、空腹血糖(FBG)、腫瘤壞死因子α(TNF α)和脂聯素水平,計算穩態模型的胰島素牴抗指數(HOMA-IR);(3)用半定量逆轉錄-聚閤酶鏈反應和Western blot檢測肝組織過氧化物酶體增殖物激活受體γ(PPAR γ)mRNA和蛋白的錶達水平.用SPSS 13.0統計軟件處理,計量資料以均數±標準差(x-±s)錶示,多組間比較用單因素方差分析,組間比較用Student-Newman-Keuls q檢驗,等級資料組間比較用秩和檢驗,脂聯素、TNF α與HOMA-IR的關聯性用直線相關分析.結果 (1)模型組大鼠造模均成功,根據肝細胞脂肪變性佔所穫肝組織標本量的範圍分為4度(F0～4),其中模型組大鼠肝細胞脂肪變程度達F3、F4的分彆有1、9隻.榦預組脂肪變性程度達F1、F2、F3的大鼠分彆有1、6、3隻.對照組大鼠肝組織炎癥活動度積分為0.模型組大鼠肝組織炎癥活動度積分為2.67±0.27,與對照組比較,U=15,P＜0.01,差異有統計學意義.榦預組炎癥活動度積分為1.36±0.12,與模型組比較,U=24,P＜0.05,差異有統計學意義.(2)對照組ALT、AST、FBG、FINS、HOMA-IR、TNF α分彆為(48.20±10.99)U/L、(153.00±45.06)U/L、(4.58±1.00)mmol/L、(10.48±1.46)μU/ml、2.13±0.29、(1.38±0.75)μg/L,模型組分彆為(114.00±19.7)U/L、(265.33±52.10)U/L、(6.58±0.86)mmoL/L、(20.73±0.91)μ U/ml、6.23±0.10、(3.47±0.19)μg/L,榦預組分彆為(78.80±15.64)U/L、(211.83±65.51)U/L、(5.38±0.88)mmol/L、(15.02±1.22)μU/ml、3.59±0.29、(1.58±0.13)μg/L,與對照組比較,模型組血清ALT、AST、FINS、FBG、HOMA-IR、TNF α升高,q值分彆為13.130、6.472、6.909、26.619、49.683、14.591,P值均＜0.01,差異有統計學意義.與模型組比較,榦預組血清ALT、FINS、FBG、HOMA-IR、TNFα降低,q值分彆為7.024、4.145、14.829、31.991、13.195,P值均＜0.01,差異有統計學意義.(3)對照組血清脂聯素、肝組織PPARγ mRNA和蛋白的錶達分彆為(8.93±0.44)mg/L、1.19±0.35、0.93±0.44,榦預組分彆為(7.12±1.00)mg/L、0.79±0.15、0.58±1.00,模型組分彆為(6.09±0.96)mg/L、0.57±0.09、0.36±0.96.對照組與模型組比較,q值分彆為10.696、8.679、16.762,P值均＜0.05,差異均有統計學意義;榦預組與模型組比較,q值分彆為3.879、3.079、6.400,P值均＜0.05,差異均有統計學意義.相關分析顯示,脂聯素水平與HOMA-IR呈負相關(r=-0.891,P＜0.01),TNFα水平與HOMA-IR呈正相關(r=0.927,P＜0.01).結論 替米沙坦可能通過促進PPARγ的錶達對NASH大鼠產生保護作用.
목적 관찰체미사탄통과격활과양화물매체증식인자활화수체γ(PPAR γ)대비주정성지방성간염대서적보호작용.방법 장30지웅성SD대서수궤분위대조조、모형조화간예조,매조10지.모형조화간예조급여고지사료위양16주유발지방성간염,기중간예조우고지위양12주후,급여체미사탄(5 mg·kg-1·d-1)관위치료4주.16주말처사대서,분별진행여하검측:(1)광학현미경하관찰간장병리변화;(2)검측혈청ALT、AST、공복이도소(FINS)、공복혈당(FBG)、종류배사인자α(TNF α)화지련소수평,계산은태모형적이도소저항지수(HOMA-IR);(3)용반정량역전록-취합매련반응화Western blot검측간조직과양화물매체증식물격활수체γ(PPAR γ)mRNA화단백적표체수평.용SPSS 13.0통계연건처리,계량자료이균수±표준차(x-±s)표시,다조간비교용단인소방차분석,조간비교용Student-Newman-Keuls q검험,등급자료조간비교용질화검험,지련소、TNF α여HOMA-IR적관련성용직선상관분석.결과 (1)모형조대서조모균성공,근거간세포지방변성점소획간조직표본량적범위분위4도(F0～4),기중모형조대서간세포지방변정도체F3、F4적분별유1、9지.간예조지방변성정도체F1、F2、F3적대서분별유1、6、3지.대조조대서간조직염증활동도적분위0.모형조대서간조직염증활동도적분위2.67±0.27,여대조조비교,U=15,P＜0.01,차이유통계학의의.간예조염증활동도적분위1.36±0.12,여모형조비교,U=24,P＜0.05,차이유통계학의의.(2)대조조ALT、AST、FBG、FINS、HOMA-IR、TNF α분별위(48.20±10.99)U/L、(153.00±45.06)U/L、(4.58±1.00)mmol/L、(10.48±1.46)μU/ml、2.13±0.29、(1.38±0.75)μg/L,모형조분별위(114.00±19.7)U/L、(265.33±52.10)U/L、(6.58±0.86)mmoL/L、(20.73±0.91)μ U/ml、6.23±0.10、(3.47±0.19)μg/L,간예조분별위(78.80±15.64)U/L、(211.83±65.51)U/L、(5.38±0.88)mmol/L、(15.02±1.22)μU/ml、3.59±0.29、(1.58±0.13)μg/L,여대조조비교,모형조혈청ALT、AST、FINS、FBG、HOMA-IR、TNF α승고,q치분별위13.130、6.472、6.909、26.619、49.683、14.591,P치균＜0.01,차이유통계학의의.여모형조비교,간예조혈청ALT、FINS、FBG、HOMA-IR、TNFα강저,q치분별위7.024、4.145、14.829、31.991、13.195,P치균＜0.01,차이유통계학의의.(3)대조조혈청지련소、간조직PPARγ mRNA화단백적표체분별위(8.93±0.44)mg/L、1.19±0.35、0.93±0.44,간예조분별위(7.12±1.00)mg/L、0.79±0.15、0.58±1.00,모형조분별위(6.09±0.96)mg/L、0.57±0.09、0.36±0.96.대조조여모형조비교,q치분별위10.696、8.679、16.762,P치균＜0.05,차이균유통계학의의;간예조여모형조비교,q치분별위3.879、3.079、6.400,P치균＜0.05,차이균유통계학의의.상관분석현시,지련소수평여HOMA-IR정부상관(r=-0.891,P＜0.01),TNFα수평여HOMA-IR정정상관(r=0.927,P＜0.01).결론 체미사탄가능통과촉진PPARγ적표체대NASH대서산생보호작용.
Objectives To investigate the effects oftelmisartan on steatohepatitis (NASH) in rats by activating peroxisome proliferator-activated receptor γ. Methods Thirty male SD rats were randomized into normal control group, NASH control group and telmisartan prevention group. Normal control group was given standard food and the other two groups were given high fat diet for 16 weeks to induce NASH. Prevention group was given telmisartan (5 mg.kg-1.d-1) for 4 weeks by intragastric adminstration after 12 weeks. At the end of the 16th week, all the rats were sacrificed. Pathological changes of liver were observed by optical microscopy.Serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), fasting blood glucose(FBG), fasting insulin(FINS), HOMA-IR(homeostasis model assessment insulin resistance), Serum TNF- α and adiponectin were detected and analyzed. Western blot and RT-PCR were used to detect PPAR γ expression in hepatic tissues on protein and mRNA levels. Results ( 1 ) Rats were successfully modeled. The liver tissue samples were divided into 4 degrees (F0 ～ 4) based on total fatty degeneration of liver cells.There was one rat reached F3 and nine rats reached F4 in NASH group, one rat reached F1, six rats reached F2 and three rats reached F3 in prevention group. Inflammatory activity scores of hepatic tissues in the model group were 2.67 ± 0.25, while that in the control group was 0 ( U= 15 and P＜ 0.01), in the prevention group were 2.67±0.25 and 1.36±0.12( U= 24 andP ＜ 0.05 ). (2) The levels of serum ALT, AST, FBG, FINS, TNF α and HOMA-IR in the model group were increased than those in the control group( the vaules ofq were 13.130, 6.472, 6.909, 26.619, 14.591 and 49.683 respectively, P ＜0.01). The levels of serum ALT, FINS, FBG, TNF α and HOMA-IR in the prevention group were decreased as compared to the model group ( the vaules ofq were 7.024, 4.145, 14.829, 13.195 and 31.991 respectively, P ＜0.01 ). (3) The serum adiponectin、 PPARγ mRNA and protein in liver tissues of the model group were lower than those in the control group ( q values were 10.696, 8.679 and 16.762 respectively,P ＜0.05 ).The data in the prevention group were higher as compared to the model group(q values were 3.879,3.079,6.400, P ＜0.05 respectively). HOMA-IR was positively correlated with the expression ofTNF α but negatively correlated with the expression of adiponectin( r = 0.927, P ＜ 0.01 ;r = -0.891, P ＜ 0.01,respectively).Conclusion Telmisartan may has preventive effect on rats with steatohepatitis (NASH) by a mechanism of activating peroxisome proliferator-activated receptor γ.
