Poster presentation. Abstract: It has been shown that lactate induces insulin resistance. However, the underlying mechanismshave not been well understood. Based on our observation that lactate augments lipopolysccharide (LPS)-stimulated inflammatory gene expression, we proposed that lactate may enhance Toll-like receptor 4 (TLR4) signaling in macrophages, which has been shown to play an important role in insulin resistance in adipocytes. In this study, we demonstrated that lactate stimulated MD-2, a co-receptor for TLR4 signaling activation, NF?B transcriptional activity, and the expression of inflammatory genes by human U937 macrophages. Similar enhancement of the inflammatory gene expression by lactate was also observed in human monocyte-derived macrophages. The essential role of MD-2 in lactate-augmented TLR4 signaling was confirmed by observation that the suppression of MD-2 expression by small interference RNA (siRNA) led to significant inhibition of inflammatory gene expression. To further elucidate how lactate treatment enhances TLR4 activation, we showed that the augmentation of inflammatory gene expression by lactate was abrogated by antioxidant treatment, suggesting a critical role of reactive oxygen species (ROS) in the enhancement of TLR4 activation by lactate. Finally, we showed that ?-cyano-4-hydroxycinnamatic acid (?-CHCA), a classic inhibitor for monocarboxylate transporters (MCTs), blocked lactate-augmented inflammatory gene expression and nuclear NF?B activity. Taken together, this study has documented that lactate boosts TLR4 activation and NF?B-dependent inflammatory gene expression via monocarboxylate transporters and MD-2 upregulation.
This study was supported by VA Merit Review grant and NIH grant DE16353 (to Y. H.). Poster design by Lisa M. Fennessy, Art Services, Medical University of South Carolina. College of Medicine. Department of Medicine. Division of Endocrinology, Diabetes & Medical Genetics