背景:非酒精性脂肪性肝病(NAFLD)与2型糖尿病(T2DM)具有共同的致病机制,晚期糖基化终产物(AGEs)上调。这里,我们的目的是研究FPS-ZM1,AGEs受体抑制剂(RAGE),小鼠肝脏中的脂质沉积。
方法:KK-Ay小鼠作为T2DM合并NAFLD的模型,而C57BL/6j小鼠为对照。此外,用DMSO(浓度为1%)处理KK-Ay小鼠,有或没有FPS-ZM1(3毫克/千克/天,i.p).使用油红O染色观察肝细胞中的脂质沉积。测量AGEs和RAGE的水平。甾醇调节元件结合蛋白-1c(SREBP-1c),以及核因子κBp65(p65nfκb)和丝裂原活化蛋白激酶p38(p38MAPK),也被发现了。
结果:与C57BL/6j小鼠相比,KK-Ay小鼠肝细胞中的脂质沉积增加。此外,不仅血浆中的AGEs水平升高,还有肝脏组织中的RAGE水平。尽管糖尿病小鼠肝脏中的总SREBP-1c水平没有变化,在患有糖尿病的KK-Ay小鼠中成熟的SREBP-1c升高。此外,糖尿病小鼠显示磷酸化p65nfκb(p-p65nfκb)和磷酸化p38MAPK(p-p38MAPK)水平升高。相反,FPS-ZM1减少肝细胞脂质沉积,以及成熟的SREBP-1c,肝组织中p-p65nfκb和p-p38MAPK水平。
结论:一般来说,FPS-ZM1可能通过下调SREBP-1c来减轻糖尿病小鼠肝细胞的脂质沉积。这可能取决于p65nfκb和p38MAPK磷酸化的下调。
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice.
METHODS: KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected.
RESULTS: Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue.
CONCLUSIONS: Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.