The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction.
The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction.
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DOI：
10.1016/j.celrep.2016.02.037
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发表时间：
2016-03-15
期刊：
影响因子：
8.8
通讯作者：
Murphy ME
中科院分区：
文献类型：
--
作者：
Kung CP;Leu JI;Basu S;Khaku S;Anokye-Danso F;Liu Q;George DL;Ahima RS;Murphy ME
P53因其肿瘤抑制作用而广为人知，但该蛋白在新陈代谢调节中的作用也鲜为人知。人类研究表明，在糖尿病和糖尿病前期的表型中，P53的第72位密码子存在一种常见的多态性。为了了解这一作用，我们利用了p53密码子72变体的人源化小鼠模型，并在高脂饮食(HFD)攻击后对这些小鼠进行了监测。携带精氨酸72(R72)P53变异体的小鼠与携带Proline 72变异体的小鼠相比，出现了更严重的肥胖和糖耐量异常(P72)。R72小鼠出现胰岛素抵抗、胰岛肥大、免疫细胞渗透增加和脂肪肝。基因表达分析和小分子抑制剂的研究表明，P53靶基因肿瘤坏死因子和NPC1L1是这种表型的基础。这些结果阐明了P53在肥胖、新陈代谢和炎症中的作用。
p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism and inflammation.