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TP53/p53 Facilitates Stress-Induced Exosome and Protein Secretion By Adipocytes

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posted on 2023-06-22, 17:07 authored by Yimao Huang, Ann V. Hertzel, Shayla R. Fish, Catherine L. Halley, Ellie K. Bohm, Hector Martell Martinez, Cameron C. Durfee, Mark A. Sanders, Reuben S. Harris, Laura J. Niedernhofer, David A. Bernlohr

Besides the secretion of fatty acids, lipolytic stimulation of adipocytes results in the secretion of triglyceride-rich extracellular vesicle (AdEVs) and some free proteins (e.g., Fatty Acid Binding Protein 4) that in sum affect adipose homeostasis as well as the development of metabolic disease. At the mechanistic level, lipolytic signals activate p53 in an ATGL-dependent manner and pharmacologic inhibition of p53 attenuates AdEV protein and FABP4 secretion. Mass spectrometry analyses of the lipolytic secretome identified proteins involved in glucose and fatty acid metabolism, translation, chaperone activities as well as redox control. Consistent with a role for p53 in adipocyte protein secretion, activation of p53 by the MDM2 antagonist nutlin potentiated AdEV particles and non-AdEV protein secretion from cultured 3T3-L1 or OP9 adipocytes while the levels of FABP4 and AdEV proteins were significantly reduced in serum from p53-/- mice compared to wild-type controls. The genotoxin doxorubicin increased AdEV protein and FABP4 secretion in a p53-dependent manner and DNA repair-depleted ERCC1-/D haploinsufficient mice expressed elevated p53 in adipose depots, along with significantly increased serum FABP4. In sum, these data suggest that lipolytic signals, and cellular stressors such as DNA damage, facilitate AdEV protein and FABP4 secretion by adipocytes in a p53-dependent manner.

Funding

Supported by NIH DK053189 to DAB. A portion of this work was carried out in the Minnesota Nano Center which receives partial support from the National Science Foundation through the NNCI program.

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