P53 activation in adipocytes of obese mice
P53 activation in adipocytes of obese mice
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DOI：
10.1074/jbc.m302364200
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发表时间：
2003-07-11
影响因子：
4.8
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Yahagi, N;Shimano, H;Yamada, N
肿瘤抑制因子p53是一种转录因子，在各种遗传毒性应激后激活或抑制其靶基因。我们以前已经表明，固醇调节元件结合蛋白-1（SREBP-1），一个关键的甘油三酯合成的转录调节因子，和脂肪生成酶在其控制下显着抑制脂肪细胞遗传肥胖ob/ob小鼠。在这里，我们证明，p53和它的靶基因是高度诱导的肥胖/肥胖小鼠在进食状态下的脂肪细胞，导致SREBP-1的负调控，从而脂肪生成基因。事实上，在ob/ob小鼠中破坏p53完全抑制了p53调节的基因至野生型水平，并部分恢复了脂肪生成酶的表达。报告基因分析表明，p53过表达抑制了SREBP-1c基因及其下游基因的启动子活性。因此，p53的激活可能构成了一个负反馈回路，防止脂肪细胞中过量的脂肪积累。总之，我们发现了p53在肥胖病理生理学中的新作用。
The tumor suppressor p53 is a transcription factor that activates or represses its target genes after various genotoxic stresses. We have previously shown that sterol regulatory element-binding protein-1 (SREBP-1), a key transcriptional regulator of triglyceride synthesis, and the lipogenic enzymes under its control are markedly suppressed in adipocytes from genetically obese ob/ob mice. Here we demonstrate that p53 and its target genes are highly induced in adipocytes of ob/ob mice in a fed state, leading to the negative regulation of SREBP-1 and thereby lipogenic genes. In fact, disruption of p53 in ob/ob mice completely suppressed the p53-regulated genes to wild-type levels and partially restored expression of lipogenic enzymes. Consistently, reporter gene analysis showed that p53 overexpression suppressed the promoter activity of the SREBP-1c gene and its downstream genes. Thus, the activation of p53 might constitute a negative feedback loop against excess fat accumulation in adipocytes. In conclusion, we discovered a novel role of p53 in the pathophysiology of obesity.