Xavier Le Guezennec1, Anna Brichkina1, Yi-Fu Huang1, Elena Kostromina2, Weiping Han2, Dmitry V Bulavin1
1 - Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
2 - Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 11 Biopolis Way, Helios, Singapore 138667.
Published in Cell Metabolism on 3rd July 2012. ( Please click here for article. )
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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 non-canonical 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 new avenues for treating obesity and atherosclerosis.
Wip1 deficiency prevents Atherosclerosis in ApoE-/- background
Gross view of aortas stained with Sudan red from apoE-/- and apoE-/- Wip1-/- mice.
For more information on Dmitry BULAVIN's laboratory, please click here.