Abstract
While the role of both elevated levels of circulating bacterial cell wall components and adipose tissue in hepatic fat accumulation has been recognized, it has not been considered that the bacterial components-recognizing adipose tissue receptors contribute to the hepatic fat content. In this study we found that the expression of adipose tissue bacterial flagellin (FLG)-recognizing Toll-like receptor (TLR) 5 associated with liver fat content (r = 0.699, p = 0.003) and insulin sensitivity (r = -0.529, p = 0.016) in humans (n = 23). No such associations were found for lipopolysaccharides (LPS)-recognizing TLR4. To study the underlying molecular mechanisms of these associations, human HepG2 hepatoma cells were exposed in vitro to the conditioned culture media derived from FLG or LPS-challenged human adipocytes. The adipocyte-mediated effects were also compared to the effects of direct HepG2 exposure to FLG and LPS. We found that the media derived from FLG-treated adipocytes stimulated fat accumulation in HepG2 cells, whereas either media derived from LPS-treated adipocytes or direct FLG or LPS exposure did not. This is likely due to that FLG-treatment of adipocytes increased lipolysis and secretion of glycerol, which is known to serve a substrate for triglyceride synthesis in hepatocytes. Similarly, only FLG-media significantly decreased insulin signaling-related Akt phosphorylation, IRS1 expression and mitochondrial respiratory chain ATP5A. In conclusion, our results suggest that the FLG-induced TLR5 activation in adipocytes increases glycerol secretion from adipocytes and decreases insulin signaling and mitochondrial functions, and increases fat accumulation in hepatocytes. These mechanisms could, at least partly, explain the adipose tissue TLR5 expression associated with liver fat content in humans.
Highlights
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, currently affecting 14–24% of the general population and up to 80% of morbidly obese individuals [1]
Correlation of Adipose Tissue TLR4, TLR5 as well as Other Toll-like receptor (TLR) and NOD-Like Receptors mRNA with Liver Fat Content and Insulin Sensitivity in Humans
TLR4 expression was not associated with liver fat content or insulin sensitivity (Fig 1B)
Summary
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, currently affecting 14–24% of the general population and up to 80% of morbidly obese individuals [1]. Our recent findings in humans suggest that adipose tissue inflammation could be the key link between the gut microbiota-derived bacterial molecules and NAFLD [3]. TLR family members are key mediators of the innate immune system They recognize bacterial surface molecules, such as lipopolysaccharides (LPS) from the outer wall of Gram-negative bacteria and flagellin (FLG), which is a structural protein of flagellum, a bacterial locomotive organelle. NRLP3 expression has been found to be increased in the adipose tissue of subjects with metabolic syndrome and insulin resistance [14], and more recently its role in regulating NAFLD progression has been recognized [10]. We hypothesized that adipose tissue expression levels of TLR4 and TLR5, and possibly other TLRs and NOD-like receptors would associate with liver fat content and insulin resistance in humans. In order to verify the associations and establish the adipocytes as a link between gut-derived molecules and hepatocytes, cell cultures were selected as a model instead of animals to eliminate any confounding factors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
