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Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting

Yong Liu1, Yizhou He2, Aiwen Jin3

  • 1Department of Radiation Oncology,Lineberger Comprehensive Cancer Center, andLaboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China;

Proceedings of the National Academy of Sciences of the United States of America
|May 30, 2014
PubMed

Insights

The RP-Mdm2-p53 pathway senses nutrient deprivation to regulate liver fat metabolism. This pathway controls malonyl-CoA decarboxylase, impacting fatty acid oxidation during fasting.

Area of Science:

  • Cellular Metabolism
  • Molecular Biology
  • Nutrient Sensing

Background:

  • The tumor suppressor p53 regulates energy metabolism.
  • In vivo signaling pathways of p53-mediated metabolic regulation are not well understood.
  • Ribosomal protein (RP) binding to Mdm2 is crucial for p53 regulation.

Purpose of the Study:

  • To investigate the in vivo role of the RP-Mdm2-p53 signaling pathway in nutrient sensing and liver lipid homeostasis.
  • To elucidate the mechanisms by which p53 influences metabolic regulation under nutrient deprivation.

Main Methods:

  • Utilized mice with a specific Mdm2 mutation (Mdm2(C305F)) affecting RP binding.
  • Analyzed liver lipid accumulation, malonyl-CoA decarboxylase (MCD) activity, and oxidative respiration under normal and fasting conditions.
  • Investigated rRNA biosynthesis and RP-Mdm2 interactions in response to nutrient deprivation.

Main Results:

  • The Mdm2(C305F) mutation promoted fat accumulation and hepatosteatosis.
  • Nutrient deprivation inhibited rRNA biosynthesis, enhanced RP-Mdm2 interaction, and induced p53-mediated MCD transactivation.
  • Fasted Mdm2(C305F) mice showed reduced MCD induction, increased malonyl-CoA, decreased oxidative respiration, and elevated fatty acid accumulation.

Conclusions:

  • The RP-Mdm2-p53 pathway is critical for sensing nutrient deprivation and maintaining liver lipid homeostasis.
  • This pathway regulates lipid partitioning by controlling MCD activity.
  • The RP-Mdm2-p53 pathway acts as an endogenous sensor stimulating fatty acid oxidation during nutrient depletion.

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