Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus
Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus
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DOI：
10.1074/jbc.274.42.30028
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发表时间：
1999-10-15
影响因子：
4.8
通讯作者：
Horton, JD
中科院分区：
文献类型：
--
作者：
Shimomura, I;Bashmakov, Y;Horton, JD
肝脂肪变性在非胰岛素依赖型糖尿病中很常见，并且在一部分个体中可能与纤维化和肝硬化相关。据报道，啮齿动物糖尿病模型的肝脏中脂肪酸合成速率增加，可能导致脂肪变性的发生。固醇调节元件结合蛋白（SREBPs）是一类调节肝脏脂质合成的转录因子。在目前的研究中，我们测量了两种糖尿病小鼠模型，肥胖ob/ob小鼠和仅在脂肪组织中过表达核SREBP-1c的转基因aP 2-SREBP-1c 436（aP 2-SREBP-1c）小鼠的肝脏中SREBP的含量。aP 2-SREBP-1c小鼠表现出类似于人类先天性全身性脂肪营养不良的综合征。两种品系的小鼠均发生高胰岛素血症、高血糖症和肝脂肪变性。与野生型小鼠相比，ob/ob和aP 2-SREBP-1c小鼠肝脏中的核SREBP-1c蛋白水平显著升高。核SREBP-1c蛋白的增加与已知参与脂肪酸生物合成的SREBP靶基因的mRNA水平升高相关，这导致体内肝脂肪酸合成速率显著升高。这些研究表明，核SREBP-1c水平的增加有助于肝脏脂肪酸合成速率的升高，导致糖尿病小鼠脂肪变性。
Hepatic steatosis is common in non-insulin-dependent diabetes and can be associated with fibrosis and cirrhosis in a subset of individuals. Increased rates of fatty acid synthesis have been reported in livers from rodent models of diabetes and may contribute to the development of steatosis. Sterol regulatory element-binding proteins (SREBPs) are a family of regulated transcription factors that stimulate lipid synthesis in liver. In the current studies, we measured the content of SREBPs in livers from two mouse models of diabetes, obese ob/ob mice and transgenic aP2-SREBP-1c436 (aP2-SREBP-1c) mice that overexpress nuclear SREBP-1c only in adipose tissue. The aP2-SREBP-1c mice exhibit a syndrome that resembles congenital generalized lipodystrophy in humans. Both lines of mice develop hyperinsulinemia, hyperglycemia, and hepatic steatosis. Nuclear SREBP-1c protein levels were significantly elevated in livers from ob/ob and aP2-SREBP-1c mice compared with wild-type mice. Increased nuclear SREBP-1c protein was associated with elevated mRNA levels for known SREBP target genes involved in fatty acid biosynthesis, which led to significantly higher rates of hepatic fatty acid synthesis in vivo. These studies suggest that increased levels of nuclear SREBP-1c contribute to the elevated rates of hepatic fatty acid synthesis that leads to steatosis in diabetic mice.