Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets
Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets
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DOI：
10.1073/pnas.97.15.8536
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发表时间：
2000-07-18
影响因子：
11.1
通讯作者：
Unger, RH
中科院分区：
文献类型：
--
作者：
Kakuma, T;Lee, Y;Unger, RH
肥胖啮齿类动物非脂肪组织中脂质的过度积累可能导致脂毒性并发症，如糖尿病。目的探讨脂肪生成转录因子固醇调节元件结合蛋白1（SREBP-1）的致病作用。我们测量了肥胖、瘦素无反应的fa/fa Zucker糖尿病肥胖大鼠的肝脏和胰岛中其mRNA。肝脏SREBP-1 mRNA是瘦+/+对照组的2.4倍，主要是因为SREBP-1c表达增加。脂肪生成酶的mRNA的范围从2.4到4.6倍高于瘦对照组，和三酰甘油（TG）含量高5.4倍。在fa/fa大鼠的胰岛中，SREBP-1c是瘦+/+ Zucker糖尿病肥胖大鼠的3.4倍。曲格列酮治疗6周可阻断未治疗fa/fa大鼠肝脏和胰岛中SREBP-1的增加，并防止糖尿病表型。SREBP-1的上调也发生在饮食诱导肥胖的Sprague-Dawley大鼠的肝脏中。通过腺病毒基因转移在瘦+/+大鼠中诱导的高瘦素血症使肝脏SREBP-1c降低74%，脂肪生成酶从35%降低到59%。总之，营养过剩增加和腺病毒诱导的高瘦素血症减少SREBP-1c在肝脏和胰岛的表达。SREBP-1过表达，这是防止曲格列酮，可能发挥作用的异位脂肪生成和脂毒性并发肥胖Zucker糖尿病大鼠。
Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1). we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Upregulation of SREBP-1 also occurred in livers of Sprague-Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic: enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.