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

Abstract

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-/Δ 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.

Burning Fat to Fuel EVs

“…While these observations suggest that AdEVs, including those that contain mitochondrial components, can have beneficial effects locally and systemically, in some circumstances AdEVs can contribute to pathology in obesity (18). It remains unknown whether the lipolysis-p53-mTORC1 pathway identified by Huang et al (12) regulates the release of specific subsets of AdEVs, whether this pathway regulates AdEV production in the endolysosomal system or at the plasma membrane, or whether these AdEVs confer beneficial and/or deleterious effects on WAT or on distant organs. Further research into these topics may reveal previously unknown biological pathways that can be targeted therapeutically to treat metabolic diseases such as obesity.…”

“…In this issue of Diabetes, Huang et al (12) report that lipolysis leads to activation of the DNA repair enzyme p53 to stimulate release of AdEVs. They demonstrate that the lipolysis-inducing compounds forskolin and isoproterenol lead to the release of EVs by 3T3-L1 adipocytes.…”