低剂量双酚A通过调控PPARγ致小鼠糖脂代谢紊乱的研究

Low-dose of bisphenol A induced glucose and lipid metabolism disorders in mice by regulating PPARγ

目的:探讨双酚A(BPA)在低剂量条件下单独或联合高脂饮食(HFD)对小鼠糖脂代谢的影响及机制。方法:60只C57BL/6J小鼠随机分为5组,建立不同浓度[1、10、100、1000μg/(kg·d)]BPA暴露的动物模型。确定最佳剂量后将另外60只C57BL/6J小鼠随机分为5组:对照组、HFD组、BPA组、BPA联合HFD组、BPA联合人参皂苷Rh1(Rh1)组。通过检测肝脏甘油三酯(TG)含量及葡萄糖耐量等指标评价小鼠糖脂代谢功能。结果:形态学实验及生化测定结果显示,小鼠在10μg/(kg·d)BPA暴露下肝脏脂质积累程度最高。与对照组相比,BPA暴露导致小鼠肝脏TG含量升高,葡萄糖耐量降低(P均<0.05)。与单纯HFD饲养小鼠相比,HFD饲养的BPA暴露小鼠肝脏TG含量升高,葡萄糖耐量降低(P均<0.05)。脂肪生成相关调控因子过氧化物酶体增殖物激活受体γ(PPARγ)、固醇调节元件结合蛋白(SREBP1)、脂肪酸合酶(FASN)和硬脂酰辅酶A去饱和酶1(SCD-1)的表达水平显著升高(P均<0.05)。使用Rh1处理BPA暴露小鼠,与单纯BPA暴露组相比,肝脏TG含量显著降低(P<0.05)。结论:BPA暴露能够诱导小鼠糖脂代谢紊乱,并加重HFD诱导的糖脂代谢紊乱。BPA调控一系列脂质代谢相关基因诱导脂质积累,引起糖脂代谢紊乱的发生。使用Rh1抑制PPARγ的表达可减轻BPA诱导的糖脂代谢紊乱。因此PPARγ转录水平的表达上调可能是BPA诱导的糖脂代谢紊乱的重要原因。

OBJECTIVE:To investigate the effect and mechanism of low doses of bisphenol A(BPA)alone or in combination with high fat diet(HFD)on glucose and lipid metabolism in mice.METHODS:Sixty C57BL/6J mice were randomly divided into five groups for exposure to BPA at different concentrations[1,10,100,1000μg/(kg·d)].After determining the optimal dose,another 60 C57BL/6J mice were randomly divided into 5 groups:control,BPA,BPA+HFD,HFD,BPA+Ginsenoside Rh1(Rh1).The function of glucose and lipid metabolism in mice was evaluated by measuring liver triglyceride(TG)content and glucose tolerance.RESULTS:After exposure of 10μg/(kg·d)BPA,morphological and biochemical determinations showed that these mice had the highest lipid accumulation.Compared with the control group,BPA exposure resulted in increased liver TG levels and decreased glucose tolerance(P<0.05).Compared with HFD group,mice from the BPA+HFD group had increased liver TG content and decreased glucose tolerance(P<0.05).Expression levels of peroxidosomal proliferator activated receptorγ(PPARγ),sterol regulatory element binding protein 1(SREBP1),fatty acid synthase(FASN)and stearyl coenzyme A desaturase 1(SCD-1),which are related to adipogenesis,were significantly increased(P<0.05).In BPA exposed mice treated with Rh1,liver TG levels were significantly reduced compared with the BPA exposed mice(P<0.05).CONSLUSION:BPA exposure induced glucose and lipid metabolism disorders in mice,and aggravate HFD-induced glucose and lipid metabolism disorders.BPA regulated a series of lipid metabolism-related genes to induce lipid accumulation,leading to the disorder of glucose and lipid metabolism.Inhibition of PPARγexpression with Rh1 significantlyalleviated BPA-induced disorders of glucose and lipid metabolism.Therefore,increased PPARγtranscriptioncould be a key reason of glucose and lipid metabolism disorder induced by BPA.