Liu Shijie, Kim Tae-Hyung, Franklin Derek A, Zhang Yanping
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA.
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA.
Cell Rep. 2017 Jan 24;18(4):1005-1018. doi: 10.1016/j.celrep.2016.12.086.
The RPL11-MDM2 interaction constitutes a p53 signaling pathway activated by deregulated ribosomal biosynthesis in response to stress. Mice bearing an MDM2 mutation that disrupts RPL11-MDM2 binding were analyzed on a high-fat diet (HFD). The Mdm2 mice, although phenotypically indistinguishable from wild-type (WT) mice when fed normal chow, demonstrated decreased fat accumulation along with improved insulin sensitivity and glucose tolerance after prolonged HFD feeding. We found that HFD increases expression of c-MYC and RPL11 in both WT and Mdm2 mice; however, p53 was induced in WT but not in Mdm2 mice. Reduced p53 activity in HFD-fed Mdm2 mice resulted in higher levels of p53 downregulated targets GLUT4 and SIRT1, leading to increased biosynthesis of NAD, and increased energy expenditure. Our study reveals a role for the RPL11-MDM2-p53 pathway in fat storage during nutrient excess and suggests that targeting this pathway may be a potential treatment for obesity.
RPL11与MDM2的相互作用构成了一条p53信号通路，该通路在应激反应中由失调的核糖体生物合成激活。对携带破坏RPL11与MDM2结合的MDM2突变的小鼠进行高脂饮食（HFD）分析。Mdm2小鼠在喂食正常食物时，其表型与野生型（WT）小鼠无明显差异，但在长期高脂饮食喂养后，脂肪堆积减少，胰岛素敏感性和葡萄糖耐量得到改善。我们发现，高脂饮食会增加WT和Mdm2小鼠中c-MYC和RPL11的表达；然而，WT小鼠中诱导了p53，而Mdm2小鼠中未诱导。高脂饮食喂养的Mdm2小鼠中p53活性降低，导致p53下调靶点GLUT4和SIRT1水平升高，从而导致NAD生物合成增加和能量消耗增加。我们的研究揭示了RPL11-MDM2-p53通路在营养过剩期间脂肪储存中的作用，并表明靶向该通路可能是治疗肥胖症的潜在方法。
