Abstract
There is strong evidence to suggest that inflammatory responses link obesity and diseases, and the understanding of obesity-induced inflammatory mechanisms is central to the pathogenesis of diseases such asnonalcoholic fatty liver disease(NAFLD) and atherosclerosis that are modified by obesity. Based on this, anti-inflammatory treatments become a potential therapies for obesity-related diseases like NAFLD.A critical role of toll-like receptor (TLR) and its downstream molecules such as tumor necrosis factor receptor-associated factor 6(TRAF6) has been documented in inflammatory response induced by fatty acid. TLR pathway regulation provides a new insight to controlling the inflammatory response induced by fatty acid. Taken together, our study was aimed to understand the mechanism of fatty acid-mediated inflammation and look for an effective target which can prevent the inflammatory response induced by obesity. In this study, we used the saturated fatty acid palmitic acid (PA) to activate TLR4 signal pathway in human monocyte cells THP-1 that established an intracellular inflammatory model. Followed with activated TLR4, downstream molecular TRAF6 was upregulated and ultimately induced proinflammatory cytokine production. Based on this model, we also found that PA downregulated miR-194 expression with TLR4 activation. Moreover, our results showed that key signal molecular TRAF6 is a target of miR-194, overexpression of miR-194 directly decreased TRAF6 expression and attenuated the release of proinflammatory cytokine TNF-α in PA-activated monocyte THP-1. We conclude that miR-194 negatively regulates the TLR4 signal pathway which is activated by PA through directly negative TRAF6 expression.
Highlights
Followed by increased consumption of foods rich in saturated fatty acid and reduced physical activity, obesity-related diseases such as nonalcoholic fatty liver disease (NAFLD) and atherosclerosis have reached epidemic proportions around the world
Results show that TLR4, TRAF6, TNF-α and TGF-β protein expressions were enhanced after exposure to palmitic acid (PA) (Figure 1c–e)
All of these results suggest that PA successfully activates the TLR4 pathway in THP-1 cells
Summary
Followed by increased consumption of foods rich in saturated fatty acid and reduced physical activity, obesity-related diseases such as nonalcoholic fatty liver disease (NAFLD) and atherosclerosis have reached epidemic proportions around the world. Expression of TNF-α, which is a common pro-inflammation cytokine, is upregulated in the pancreatic islets of patients and animal models with obesity [2,3]. The potential molecular between free fatty acids and obesity-related diseases is the toll-like receptors (TLRs). Recent studies indicated that TLR4 signaling is important for fatty acid-mediated inflammatory response [7]. Saturated fatty acids activating the inflammation via TLR4 in macrophage had been identified by Lee et al and Suganami and Ogawa, respectively [8,9]. Saturated fatty acids serve as a natural endogenous ligand of TLR4, thereby activating downstream signal molecules, such as TRAF6, to mediated proinflammatory transcription factor nuclear factor-kappaB (NF-κB) activation and pro-inflammatory cytokines such as TNF-α production [10]
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