Tributyltin triggers lipogenesis in macrophages via modifying PPARγ pathway

Tributyltin (TBT), a bioaccumulative and persistent environmental pollutant, has been proposed as a metabolism disruptor and obesogen through targeting peroxisome proliferator-activated receptor gamma (PPAR gamma) receptor pathway. However, it remains unknown whether this biological effect occurs in macrophage, a cell type which cooperates closely with hepatocytes and adipocytes to regulate lipid metabolism. This study for the first time investigated the effect of TBT on PPAR gamma pathway in macrophages. Our results indicated that nanomolar levels of TBT was able to strongly activate PPAR gamma in human macrophages. TBT treatment also markedly increased the intracellular lipid accumulation, and enhanced the expression of lipid metabolism-related genes in macrophages, while these effects were all significantly down-regulated in PPAR gamma-deficient macrophages, confirming the involvement of PPAR gamma in TBT-induced lipogenesis. Next, a mouse model that C57BL/6 mice were orally exposed to TBT with the doses (250 and 500 mu g/kg body weight) lower than NOAEL (no observed adverse effect level) was used to further investigate the in vivo mechanisms. And the in vivo results were consistent with cellular assays, confirming the induction of PPAR gamma and the increased expression of lipogenesis-regulating and lipid metabolism-related genes by TBT in vivo. In conclusion, this study not only provided the first evidence that TBT stimulated lipogenesis, activated PPAR gamma and related genes in human macrophages, but also provided insight into the mechanism of TBT-induced metabolism disturbance and obesity through targeting PPAR gamma via both in vitro cellular assays and in vivo animal models. (C) 2020 Elsevier Ltd. All rights reserved.

Automated summary

This study revealed that TBT can strongly activate PPAR gamma in human macrophages, leading to increased lipid accumulation and expression of lipid metabolism-related genes. The involvement of PPAR gamma in TBT-induced lipogenesis was confirmed by the down-regulation of effects in PPAR gamma-deficient macrophages. The findings suggest a potential mechanism for TBT-induced metabolism disturbance and obesity through targeting PPAR gamma.