A FABP4-PPAR? signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes.

ABSTRACT: Nitro-fatty acids (NO2-FA) are electrophilic lipid mediators derived from unsaturated fatty acid nitration. These species are produced endogenously by metabolic and inflammatory reactions and mediate anti-oxidative and anti-inflammatory responses. NO2-FA have been postulated as partial agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPAR?), which is predominantly expressed in adipocytes and myeloid cells. Herein, we explored molecular and cellular events associated with PPAR? activation by NO2-FA in monocytes and macrophages. NO2-FA induced the expression of two PPAR? reporter genes, Fatty Acid Binding Protein 4 (FABP4) and the scavenger receptor CD36, at early stages of monocyte differentiation into macrophages. These responses were inhibited by the specific PPAR? inhibitor GW9662. Attenuated NO2-FA effects on PPAR? signaling were observed once cells were differentiated into macrophages, with a significant but lower FABP4 upregulation, and no induction of CD36. Using in vitro and in silico approaches, we demonstrated that NO2-FA bind to FABP4. Furthermore, the inhibition of monocyte FA binding by FABP4 diminished NO2-FA-induced upregulation of reporter genes that are transcriptionally regulated by PPAR?, Keap1/Nrf2 and HSF1, indicating that FABP4 inhibition mitigates NO2-FA signaling actions. Overall, our results affirm that NO2-FA activate PPAR? in monocytes and upregulate FABP4 expression, thus promoting a positive amplification loop for the downstream signaling actions of this mediator.

SUBMITTER: Lamas Bervejillo M 

PROVIDER: S-EPMC6926352 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature