Cell Metab：Wip1磷酸酶敲除可改善肥胖和动脉粥样硬化

在西方国家，肥胖和动脉粥样硬化相关疾病占死亡率的1/3，其分子机制仍然不完全清楚。近日，新加坡研究人员发现敲除Wip1磷酸酶基因可改善肥胖和动脉粥样硬化。研究论文发表在7月3日的Cell Metabolism杂志上。

Wip1磷酸酶是Atm信号途径中的一个分子，它在脂肪聚集和动脉硬化中发挥重要作用，Wip1敲除的小鼠肥胖和动脉粥样硬化都得到改善。研究发现，Wip1磷酸酶可促进体重的上升和脂肪的累积，而敲除Wip1可阻止高脂诱导的肥胖，并可阻止巨噬细胞向泡沫细胞的转化，由此阻止了动脉粥样硬化斑块的形成。在ApoE-/-背景下，Wip1的缺失也可避免高血压的发生。

此项研究成果或许可以为肥胖和动脉粥样硬化的治疗开辟道路。

doi:10.1016/j.cmet.2012.06.003
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Wip1-Dependent Regulation of Autophagy, Obesity, and Atherosclerosis

Xavier Le Guezennec1, Anna Brichkina1, Yi-Fu Huang1, Elena Kostromina2, Weiping Han2, Dmitry V. Bulavin

Obesity and atherosclerosis-related diseases account for over one-third of deaths in the western world. Controlling these conditions remains a major challenge due to an incomplete understanding of the molecular pathways involved. Here, we show that Wip1 phosphatase, a known negative regulator of Atm-dependent signaling, plays a major role in controlling fat accumulation and atherosclerosis in mice; specifically, Wip1 deficiency prevents both conditions. In the course of atherosclerosis, deletion of Wip1 results in suppression of macrophage conversion into foam cells, thus preventing the formation of atherosclerotic plaques. This process appears to be independent of p53 but rely on a noncanonical Atm-mTOR signaling pathway and on selective autophagy in regulation of cholesterol efflux. We propose that the Wip1-dependent control of autophagy and cholesterol efflux may provide avenues for treating obesity and atherosclerosis.