PPARδ激动剂对非酒精性脂肪肝大鼠胰岛素抵抗作用的研究

Research on the protection effect of PPARδ agonist for non-alcoholic fatty liver disease in rats

目的研究PPARδ激动剂(GW501516)对高脂饮食诱导的非酒精性脂肪肝(NAFLD)大鼠胰岛素抵抗的影响及特点。方法 47只SD雄性大鼠随机分为造模组(n=37)与正常对照组(n=10),分别给予高脂饮食和普通饮食喂养12周后,造模组随机处死3只大鼠,经肝脏病理HE染色观察造模成功。余34只造模成功大鼠随机分为:模型组(n=10)、GW501516治疗组(n=12),吡格列酮治疗组(n=12)。治疗2周、4周后分别处死各组半数大鼠。测体质量、肝重、体长并计算肝指数及体质量指数(BMI);采集血清检测空腹血糖、肝功、血脂,放免法测空腹胰岛素,计算胰岛素敏感指数HOMA-IR;行肝组织油红O染色、HE染色;ELISA法测血清IGF-1;免疫组化检测SREBP-1c及GLUT-2表达情况。结果 (1)与模型组相比,GW501516治疗组肝湿重、体质量、肝指数及BMI均下降在治疗4周后更为明显(P<0.05);治疗4周后,GW501516组体质量和BMI较吡格列酮治疗组低(P<0.05)。(2)与模型组相比,GW501516治疗组糖代谢、脂代谢及肝功均明显改善(P<0.05);治疗4周后,GW501516组糖代谢、脂代谢及肝功改善较格列酮治疗组更为明显(P<0.05)。(3)与模型组相比,GW501516治疗2周及4周后肝脏脂肪变及炎症均明显减轻;治疗4周后,GW501516组肝脏组织改善程度较吡格列酮治疗组更明显。(4)与模型组相比,GW501516治疗组血清IGF-1水平升高、肝脏SREBP-1c表达下调、GLUT-2表达上调(P<0.05);治疗4周后,与吡格列酮治疗组相比,GW501516组IGF-1及GLUT-2升高更明显,SREBP-1c降低更明显(P<0.05)。结论 PPARδ激动剂GW501516可通过上调IGF-1及GLUT-2、下调SREBP-1c改善NAFLD大鼠的胰岛素抵抗及减轻肝脏脂质沉积,且改善作用明显优于PPARγ激动剂(吡格列酮)。

Objective To investigate the effect and characteristic of PPARδ agonist （GW501516） on non-alcoholic fatty liver disease induced by a high-fat diet in the rats.Methods Forty-Seven male Sprague-Dawley （SD） rats were randomly divided into normal control group （n =10）,model group （n =10）,GW501516 treatment group （n =12）,pioglitazone treatment group （n =12）.Drug treatments began when the model was successfully established and the rats were sacrificed after treatment for 2 weeks and 4 weeks.Hepatic wet weight and body weight were measured and hepatosomatic index and body mass index （BMI） were calculated.Histopathological and biochemical analysis were carried.Fasting blood glucose and fasting insulin were detected and homeostasis model assessment （HOMA-IR） was calculated.ELISA was used to measure the serum IGF-1 level.Immunohistochemistry was used to detect protein expression of SREBP-1c and GLUT-2 in liver.Results （1） Compared with model group,hepatic wet weight,body weight,hepato-somatic index and BMI in GWS01516 treatment group decreased and especially after treatment for 4 weeks （P ＜ 0.05）.After treatment for 4 weeks,body weight and BMI in GW501516 treatment group were lower than pioglitazone treatment group （P ＜ 0.05）.（2） Compared with model group,indexes of glucose metabolism,lipid metabolism and liver function in GW501516 treatment group significantly improved （P ＜ 0.05）.After treatment for 4 weeks,indexes of glucose metabolism,lipid metabolism and liver function in GW501516 treatment group significantly improved than pioglitazone treatment group （P ＜ 0.05）.（3） Compared with model group,hepatic steatosis and inflammation in GW501516 treatment group significantly reduced （P ＜ 0.05）.After treatment for 4 weeks,hepatic steatosis and inflammation in GW501516 treatment group significantly reduced than pioglitazone treatment group （P ＜ 0.05）.（4） Compared with model group,the level of serum IGF-1 and expression of hepatic GLUT-2 in GW501516 treatment group significantly upregulated （P ＜ 0.05） and the expression of hepatic SREBP-1 c in GW501516 treatment group significantly down-regulated （P ＜ 0.05）.After treatment for 4 weeks,the level of serum IGF-1 and expression of hepatic GLUT-2 in GW501516 treatment group significantly up-regulated than pioglitazone treatment group （P ＜ 0.05） and expressions of hepatic SREBP-1c in GW501516 treatment group significantly down-regulated than pioglitazone treatment group （P ＜ 0.05）.Conclusion PPARδ agonist （GW501516） can up-regulate IGF-1,GLUT-2 and down-regulate SREBP-1c to improve insulin resistance and hepatic steatosis and is better than PPARγ agonist （pioglitazone）.