线粒体靶向小分子IR-61改善小鼠非酒精性脂肪肝

Effect of mitochondrial targeting small molecule IR-61 in attenuating non-alcoholic fatty liver in mice

目的探讨线粒体靶向七甲川花菁类荧光小分子IR-61对小鼠非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)模型的治疗效果。方法通过喂养高脂饲料建立NAFLD小鼠模型,腹腔注射磷酸缓冲盐溶液(phosphate buffer saline,PBS)或IR-61,治疗18周后,取肝脏组织切片HE常规染色,显微镜下观察,采用酶比色法检测肝脏和血清甘油三酯(triglyceride,TG)含量,Real-time PCR和Western blot法检测固醇调节元件结合蛋白1c(sterol regulatory element binding protein 1c,SREBP-1c)、乙酰辅酶A羧化酶1(acetyl-Co A carboxylase-1,ACC1)、过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor-α,PPARα)和肉毒碱棕榈酰转移酶-1(carnitine palmitoyltransferase-1,CPT1)的mRNA及蛋白表达水平。结果 IR-61可降低高脂诱导的小鼠肝脏TG含量增加,抑制SREBP-1c、ACC1过度表达;同时增加肝脏PPARα、CPT1的表达(P<0.05);IR-61可明显改善小鼠肝脏的脂肪沉积。结论 IR-61通过抑制高脂诱导的脂肪合成代谢过度增强,促进肝脏脂肪酸氧化,减少肝脏甘油三酯沉积,从而改善非酒精性脂肪肝。

Objective To investigate the therapeutic effect of IR-61, a mitochondrial targeting heptamethine cyanine dye, on non-alcoholic fatty liver disease （NAFLD） in a mouse model. Methods Mouse model of NAFLD was established by feeding the mice with a high-fat diet. After the modeling, the mice were treated with intraperitoneal injection of PBS or IR-61 （25 IxL/g） once a week for 18 consecutive weeks. HE staining was used to observe the pathological changes in liver tissues, and liver and serum levels of triglyceride （TG） were measured using enzyme eolorimetry. Real-time PCR and Western blotting were used to detect the expression levels of sterol regulatory element-binding protein-le （SREBP-1c）, aeetyl-CoA carboxylase-1 （ACC1）, peroxisome proliferator-aetivated receptor-α （PPARα） and earnitine palmitoyltransterase-1 （ CPT1 ）. Results IR-61 treatment reduced high-fat feeding-induced elevation of TG level in the liver of the mice and inhibited the high expression of SREBP-le and ACC1. IR-61 significantly increased the expression of PPARa and CPT1 in the liver （P 〈 0.05） and markedly improved fatty degeneration of the liver in mice after high-fat feeding. Conclusion IR-61 inhibits high-fat feeding-induced increase in fat synthesis, enhances liver fatty acid oxidation, and thereby reduces hepatic TG deposition and improves NAFLD in mice.