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过氧化物酶体增殖物激活受体α/γ双重激动剂西格列他扎改善了新生期谷氨酸单钠处理肥胖大鼠的胰岛素抵抗和血脂异常。

The PPARalpha/gamma dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats.

作者信息

Li Ping-Ping, Shan Song, Chen Yue-Teng, Ning Zhi-Qiang, Sun Su-Juan, Liu Quan, Lu Xian-Ping, Xie Ming-Zhi, Shen Zhu-Fang

机构信息

Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

出版信息

Br J Pharmacol. 2006 Jul;148(5):610-8. doi: 10.1038/sj.bjp.0706745. Epub 2006 Jun 5.

Abstract
  1. The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARalpha. 2. Chiglitazar is a PPARalpha/gamma dual agonist. 3. The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4. Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5. Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARalpha, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6. These data suggest that PPARalpha/gamma coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARgamma agonists.
摘要
  1. 本研究旨在探讨西格列他扎改善谷氨酸钠(MSG)肥胖大鼠胰岛素抵抗和血脂异常的能力,并确定其降脂作用是否通过激活PPARα介导。2. 西格列他扎是一种PPARα/γ双重激动剂。3. 该化合物改善了受损的胰岛素和葡萄糖耐量;降低了血浆胰岛素水平,增加了胰岛素敏感性指数并降低了HOMA指数。正常血糖高胰岛素钳夹研究表明,西格列他扎增加了MSG肥胖大鼠的葡萄糖输注率。4. 西格列他扎抑制丙氨酸糖异生,降低了MSG肥胖大鼠的肝糖原水平。与罗格列酮一样,西格列他扎促进脂肪细胞分化并减小脂肪细胞的最大直径。此外,西格列他扎减少了胰岛中的纤维化和脂质积累,并增加了胰岛大小。5. 西格列他扎降低了血浆甘油三酯、总胆固醇(TCHO)、非酯化脂肪酸(NEFA)和低密度脂蛋白胆固醇水平;降低了肝脏甘油三酯和TCHO含量;降低了肌肉NEFA水平。与罗格列酮不同,西格列他扎使MSG肥胖大鼠肝脏中PPARα、CPT1、BIFEZ、ACO和CYP4A10的mRNA表达显著增加。6. 这些数据表明,PPARα/γ共同激动剂,如西格列他扎,以与罗格列酮不同的机制影响脂质稳态,西格列他扎对糖尿病患者脂质稳态的影响可能优于选择性PPARγ激动剂。

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