Abstract
BackgroundToll-like receptor 4 (TLR4) contributes to the development of NAFLD (nonalcoholic fatty liver disease) and MetS (metabolic syndrome). It is unclear whether anti-diabetic metformin affects TLR4 expression on blood monocytes, thereby protecting or improving inflammatory parameters. Therefore, we investigated TLR4 in patients with NAFLD meeting different sets of MetS criteria and linked the results with the disease burden.Methods70 subjects were characterized and divided into three groups: (I) healthy individuals, (II) nonobese with NAFLD and without MetS, and (III) prediabetic, obese with NAFLD and MetS. We determined the concentrations of IL-1β, IL-6, TNFα, and monocyte TLR4 levels in fresh blood as well as in blood cultures with or without metformin supplementation.ResultsThe characteristics of the study groups revealed a significant association between NAFLD and BMI, MetS and inflammatory parameters, and TLR4. In ex vivo studies, 100 μM of metformin decreased the TLR4 level by 19.9% (II group) or by 35% (III group) as well as IL-1β and TNFα production. A stepwise multiple regression analysis highlighted a strong effect of metformin on attenuation of the link between TLR4 and NAFLD, and TNFα.ConclusionWe concluded that, by attenuation of the blood monocyte TLR4 level, metformin reduced their inflammatory potential—critical after recruitment these cells into liver. However, this finding should be confirmed after in vivo metformin administration.
Highlights
Westernized diet and lifestyle are responsible for globalization of obesity—the main risk factor of co-morbidities such as nonalcoholic fatty liver disease (NAFLD), metabolic syndrome (MetS), cardiovascular disease (CVD), and cancer
The characteristics of the study groups revealed a significant association between NAFLD and body mass index (BMI), MetS and inflammatory parameters, and Toll-like receptor 4 (TLR4)
A stepwise multiple regression analysis highlighted a strong effect of metformin on attenuation of the link between TLR4 and NAFLD, and TNFα
Summary
Westernized diet and lifestyle are responsible for globalization of obesity—the main risk factor of co-morbidities such as nonalcoholic fatty liver disease (NAFLD), metabolic syndrome (MetS), cardiovascular disease (CVD), and cancer. Nonbacterial substances may function as TLR4 ligands i.e. free fatty acids (FFAs) [6, 7]; some reports have indicated that FFAs do not activate TLR4 directly [8] Both NAFLD and obesity are characterized by increased circulating endotoxin and FFA levels [8] as well as enhanced TLR4 expression on liver cells (mainly Kupffer cells) [5, 9] and blood leukocytes (mainly monocytes) [10]. Toll-like receptor 4 (TLR4) contributes to the development of NAFLD (nonalcoholic fatty liver disease) and MetS (metabolic syndrome). It is unclear whether anti-diabetic metformin affects TLR4 expression on blood monocytes, thereby protecting or improving inflammatory parameters. We investigated TLR4 in patients with NAFLD meeting different sets of MetS criteria and linked the results with the disease burden
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