Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver
Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver
复制标题
DOI：
10.1074/jbc.m306540200
复制
发表时间：
2003-09-19
影响因子：
4.8
通讯作者：
Hammer, RE
中科院分区：
文献类型：
--
作者：
Horton, JD;Shimomura, I;Hammer, RE
固醇调节元件结合蛋白（SREBPs）是一类调节胆固醇和脂肪酸稳态的膜结合转录因子。在哺乳动物中，已经鉴定了三种SREBP亚型，命名为SREBP-1a、SREBP-1c和SREBP-2。SREBP-1a和SREBP-1c通过选择性剪接的第一外显子来源于相同的基因。SREBP-1a具有更长的转录激活结构域，并且在培养细胞和肝脏中是比SREBP-1c更有效的转录激活因子。在这里，我们描述了使用脂肪细胞特异性aP 2启动子（aP 2-nSREBP-1a）在小鼠脂肪细胞中过表达核形式SREBP-1a（nSREBP-1a）的生理后果。转基因aP 2-nSREBP-1a小鼠发育出明显增大的白色和棕色脂肪细胞，这些脂肪细胞已完全分化。从aP 2-nSREBP-1a小鼠分离的脂肪细胞具有显著增加的脂肪酸合成速率和增强的脂肪酸分泌。脂肪细胞中脂肪酸的产生和释放增加，进而导致脂肪肝。替代SREBP-1同种型nSREBP-1c在脂肪组织中的过表达抑制脂肪细胞分化;结果，转基因nSREBP-1c小鼠产生类似于人脂肪营养不良的综合征，其包括外周白色脂肪组织的损失、糖尿病和脂肪肝（Shimomura，I.，哈默河E、理查德森，J.A.，池本，S.，Bashmakov，Y.，戈尔茨坦，J.L.，Brown，M. S.（1998）Genes Dev. 12，3182-3194）。与此形成鲜明对比的是，nSREBP-1a在脂肪中的过表达导致完全分化的脂肪细胞肥大，没有糖尿病和轻度肝脂肪变性。这些结果表明nSREBP-1a和nSREBP-1c在体内脂肪细胞脂肪代谢中具有不同的作用。
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. ( 1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.