Abstract
Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.
Highlights
Insulin resistance (IR) has been shown to be the common pathogenesis of many metabolic diseases, such as obesity, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, and metabolic syndrome [1, 2]
Papackova et al reported that removal of the Kupffer cells by barium chloride prevents metabolic inflammation and insulin resistance in the liver caused by high-fat diet and reduces circulating inflammation and systemic insulin resistance [8, 9], suggesting that the Kupffer cells may play the key role in the pathogenesis in metabolic inflammation and insulin resistance
Compared with normal diet controls (NC), the expression of F4/80 and Cd11c mRNA was upregulated in the liver of high-fat diet controls (HM) and high-fat diet controls with empty vector transfection (HC), and these changes were attenuated with Toll-like receptor 4 (TLR4) (HT) and Activated protein 1 (AP1) (HA) siRNA transfection (Figures 1(c) and 1(d))
Summary
Insulin resistance (IR) has been shown to be the common pathogenesis of many metabolic diseases, such as obesity, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, and metabolic syndrome [1, 2]. Mediators of Inflammation type inflammatory polarization and the activation of inflammatory pathway in major insulin target organs such as the liver and adipose tissue are critical in the pathogenesis of metabolic inflammation [4]. The liver is a key metabolic organ, and insulin resistance in the liver is increasingly considered to play a crucial role in the etiology of these metabolic disorders, in which metabolic stress in the liver can induce immune activation and mediate metabolic abnormalities [5, 6]. In insulin resistant mice developed by high-fat diet feeding, intrahepatic macrophages are mainly characterized by M1-type polarization, which induces metabolic inflammation and mediates hepatic insulin resistance [7]. It is very important to investigate intervention target to attenuate the Kupffer cell inflammatory activation in the prevention and treatment of metabolic inflammation and hepatocyte insulin resistance
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