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

Besides the secretion of fatty acids, lipolytic stimulation of adipocytes results in the secretion of triglyceride-rich extra¬cellular vesicles and some free proteins (e.g., fatty acid bind¬ing 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 adipose triglyceride lipase-dependent manner, and pharmacologic inhibition of p53 attenuates adipocyte-derived extracellular vesicle (AdEV) protein and FABP4 secretion. Mass spectrometry analyses of the lipolytic secretome identified proteins involved in glucose and fatty acid metabolism, translation, chaperone activities, and 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 se¬cretion from cultured 3T3-L1 or OP9 adipocytes while the lev¬els of FABP4 and AdEV proteins were significantly reduced in serum from p53_/_ mice compared with wild-type controls. The genotoxin doxorubicin increased AdEV protein and FABP4 secretion in a p53-dependent manner and DNA repair-depleted ERCC1 ~/A-haploinsuff icient mice expressed elevated p53 in adipose depots, along with significantly in¬creased serum FABP4. In sum, these data suggest that lipo¬lytic signals, and cellular stressors such as DNA damage, facilitate AdEV protein and FABP4 secretion by adipocytes in a p53-dependent manner.