二苯乙烯苷经 PPAR α信号通路激活自噬治疗大鼠高脂性脂肪肝的作用研究
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国家自然科学基金(81202879)


Therapeutic effect of 2,3,4’,5⁃tetrahydroxystilbene⁃2⁃O⁃β⁃D⁃glucoside on hyperlipidemic fatty liver in rats by activating PPAR α pathway of autophagy
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    摘要:

    目的:观察二苯乙烯苷(TSG)对高脂性脂肪肝大鼠的治疗作用,并从PPAR α信号通路研究其可能的作用机制。方法:将雄性SD大鼠随机分为正常组、模型组、TSG(80 mg/kg)组、MK886+ TSG(80 mg/kg)组。采用高脂饮食建立大鼠高脂性脂肪肝模型,给予二苯乙烯苷治疗6周,然后测定血清和肝组织中总胆固醇(TC)、甘油三酯(TG)和游离脂肪酸(FFA)水平,测定肝重系数及血清中丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)水平;光镜检查肝脏的病理形态学改变。同时采用Western blot法检测各组大鼠肝脏中过氧化物酶体增殖物激活受体α(PPAR α)、自噬相关蛋白LC3Ⅰ、LC3Ⅱ、Beclin 1及p62的表达情况。结果:与模型组相比,TSG给药6周后,能显著降低脂肪肝大鼠血清中TC、TG和FFA水平,肝组织中TG、FFA含量和肝重系数,及血清中ALT和AST水平(P<0.05或P<0.01);同时病理检查结果显示,TSG给药组大鼠肝组织脂肪变性明显减轻。Western blot检测结果显示,TSG可明显上调肝组织中PPAR α蛋白的表达,上调LC3Ⅱ、Beclin 1蛋白的表达,并下调p62的表达(P<0.01)。当预先使用PPAR α拮抗剂MK886时,TSG的作用明显减弱或消失。结论:TSG对高脂性脂肪肝大鼠具有明显的治疗作用,其机制可能与通过激活PPAR α后,上调LC3Ⅱ、Beclin 1和下调p62的蛋白表达而激活细胞自噬,从而促进脂滴的降解,改善肝脏脂质代谢紊乱有关。

    Abstract:

    Objective:To observe the effect of 2,3,4’,5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) on hyperlipidemic fatty liver in rats,and explore the potential mechanisms by PPAR α signaling pathway. Methods:SD rats were randomly divided into control group,model group,TSG 80 mg/kg group,MK886 plus TSG 80 mg/kg group. The rat model was established by orally feeding high-fat emulsion for 4 weeks. Then TSG was administered to these rats for 6 weeks. TC,TG and FFA levels in serum and hepatic tissues,hepatic weight coefficient,the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in serum were measured;and the hepatic histopathological changes were observed. Meanwhile,the expressions of PPAR α,LC3Ⅰ,LC3Ⅱ,Beclin 1 and p62 proteins in hepatic tissues were measured by Western blot. Results:Compared with the model group,TSG could significantly decrease TC,TG and FFA levels in serum,TG and FFA contents in hepatic tissues,hepatic weight coefficient,and also the serum levels of ALT and AST(P<0.05 or P<0.01). Meanwhile,the histological evaluation of liver specimens revealed that lipid accumulation in TSG-treated group was obviously ameliorated. Western blot results showed that TSG could markedly up-regulated the expressions of hepatic PPAR α,LC3Ⅱ,Beclin 1 proteins,and down-regulated the expression of p62(P<0.05 or P<0.01). However,the effect of TSG was weakened or cancelled when pretreatment with PPAR α antagonist MK886. Conclusion:TSG was effective in treating hyperlipidemic fatty liver in rats,and its mechanism might be related to the up-regulation of LC3Ⅱ and Beclin 1 protein expressions,down-regulation of p62 protein expression to activate autophagy by activation of PPAR α,and eventually to improve lipid metabolism.

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赵 喜,王小蓉,程金妹,陈爱春.二苯乙烯苷经 PPAR α信号通路激活自噬治疗大鼠高脂性脂肪肝的作用研究[J].南京医科大学学报(自然科学版),2018,(12):1679-1682,1687

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  • 收稿日期:2018-08-13
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  • 在线发布日期: 2019-01-02
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