Wip1-dependent regulation of autophagy, obesity, and atherosclerosis

Cell Metab. 2012 Jul 3;16(1):68-80. doi: 10.1016/j.cmet.2012.06.003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / genetics
  • Ataxia Telangiectasia Mutated Proteins
  • Atherosclerosis / enzymology*
  • Atherosclerosis / etiology
  • Atherosclerosis / pathology
  • Autophagy*
  • Cell Cycle Proteins / metabolism
  • Cholesterol / metabolism
  • Cholesterol Esters / metabolism
  • DNA-Binding Proteins / metabolism
  • Diet, High-Fat / adverse effects
  • Female
  • Foam Cells / metabolism
  • Intra-Abdominal Fat / pathology
  • Liver X Receptors
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / enzymology*
  • Obesity / etiology
  • Obesity / pathology
  • Orphan Nuclear Receptors / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Phosphoprotein Phosphatases / physiology*
  • Protein Phosphatase 2C
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Weight Gain

Substances

  • Apolipoproteins E
  • Cell Cycle Proteins
  • Cholesterol Esters
  • DNA-Binding Proteins
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Cholesterol
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • Phosphoprotein Phosphatases
  • Ppm1d protein, mouse
  • Protein Phosphatase 2C