Research ArticleUric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism
Introduction
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased triglyceride accumulation in hepatocytes as a consequence of metabolic disorders [1], [2]. NAFLD ranges from simple steatosis to steatohepatitis (NASH), and may eventually lead to cirrhosis and hepatocellular carcinoma [1], [2]. According to recent statistics, NAFLD has become one of the most common chronic liver diseases worldwide. The disease affects 31–46% of adults in the United States [3].
NAFLD is recognized as hepatic manifestation of metabolic syndrome (MS) [4]. There is growing concern for the association between NAFLD and MS. NAFLD is frequently associated with obesity, type 2 diabetes, dyslipidemia, and insulin resistance [5], [6], which are the main features of MS [7]. Furthermore, insulin resistance is increasingly recognized as a key factor linking NAFLD and MS [4], [5], [6]. NAFLD may also be considered as an additional feature of MS, with specific hepatic insulin resistance [4], [5], [6]. It is reported that more than 70% of MS patients have NAFLD [8]. Meanwhile, about 90% of NAFLD patients have more than one MS components [5].
Hyperuricemia or high serum uric acid levels have been linked to metabolic disorders including obesity, and type 2 diabetes [9], [10]. Recent studies also reported a significant relationship between hyperuricemia and insulin resistance [11], [12]. In addition, a body of research has revealed a close relationship between uric acid and NAFLD. We previously reported that serum uric acid levels were significantly elevated in NAFLD patients [13]. Further research by our group indicated that elevated serum uric acid levels in healthy individuals independently predicts an increased incidence of NAFLD [14]. However, epidemiological studies were unable to clarify whether elevated serum uric acid is a cause or merely an innocent bystander of NAFLD; neither the functional role nor the molecular mechanisms behind this association is known.
Recently, increasing attentions have been paid to the mechanisms by which uric acid promotes the development of NAFLD and insulin resistance. One study showed that uric acid-induced hepatic steatosis through the generation of mitochondrial oxidative species, which further increased de novo lipogenesis in cultured HepG2 cells [15]. Other research revealed an additional mechanism, namely that uric acid-induced fat accumulation through SREBP-1 activation induced by endoplasmic reticulum stress [16]. Yet another study revealed that uric acid-induced insulin resistance and impaired insulin signaling through a reactive oxygen species-related pathway both in vivo and in vitro [17]. However, the previous studies showed no evidence whether uric acid-induced hepatic steatosis in vivo. Further clarification of the effects and exact mechanisms of uric acid on NAFLD may provide valuable clues for understanding the pathogenesis of NAFLD.
The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that can recognize pathogen- and danger-associated molecular patterns [18]. NLRP3 activation leads to the production and secretion of IL-1β and IL-18 [18]. Previous studies reported that uric acid can activate the NLRP3 inflammasome [19], [20]. The NLRP3 inflammasome plays a central role in obesity and insulin resistance [21], [22], [23], and it is also involved NAFLD development [23], [24]. However, the specific mechanisms by which NLRP3 inflammasome participates in uric acid-induced hepatic steatosis and insulin resistance are not known.
In this study, we analyzed whether uric acid induces NLRP3 inflammasome activation, hepatic steatosis, and insulin resistance both in vivo and in vitro, and investigated whether modulation of this induction could alleviate hepatic fat accumulation and insulin resistance.
Section snippets
Materials and methods
Firstly, we analyzed the impact of uric acid on development of hepatic steatosis and insulin resistance. Then, we studied the role of the NLRP3 inflammasome in uric acid-induced fat accumulation and insulin signaling impairment. Detailed materials and methods are described in Supplementary materials and methods.
Uric acid directly induces fat accumulation in hepatocytes
To investigate whether uric acid has a causal role in the development of hepatic steatosis, we established a mouse model of hyperuricemia by feeding C57BL/6 mice for eight weeks with hyperuricemia-inducing diet (HUA) consisting of 2% oxonic acid, 3% uric acid and 95% standard chow. Oxonic acid is an uricase inhibitor that is commonly used for establishing animal models of hyperuricemia [25], [26]. HUA-fed mice showed significantly higher serum uric acid and triglyceride levels than standard
Discussion
In this study, we investigated the effects and underlying mechanisms of uric acid in the development of NAFLD and insulin resistance. We found that uric acid directly induces fat accumulation and insulin resistance both in vivo and in vitro. In addition, we found that uric acid regulates activation of the NLRP3 inflammasome, which is essential for the effects of uric acid on hepatic steatosis and insulin signaling.
The development of NAFLD is a complex process resulting from the interactions of
Financial support
This work was supported by National Key Basic Research Development Program (No. 2012CB524905 to Y.L.), National Science and Technology Support Plan Project (No. 2012BAI06B04 to Y.L.), National Natural Science Foundation of China (Nos. 81100278 and 81470838 to C.X., 81170378 and 81230012 to Y.L., and 81270487 to C.Y.), Zhejiang Provincial Natural Science Foundation of China (No. LR15H030001 to C.X.), International Science and Technology Cooperation Projects of Zhejiang Province (No. 2013C24010
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
Authors’ contributions
Study concept and design: X. Wan, C. Xu, Y. Li, and C. Yu. Acquisition of data: X. Wan, Y. Lin, C. Lu, D. Li, J. Sang, H. He, and X. Liu. Analysis and interpretation of data: X. Wan, C. Xu, Y. Li, and C. Yu. Drafting of the manuscript: X. Wan, C. Xu, Y. Li, and C. Yu. Critical revision of the manuscript for important intellectual content: Y. Li, and C. Yu. Statistical analysis: X. Wan, and C. Xu. Obtained funding: C. Xu, Y. Li, and C. Yu. Administrative, technical, or material support: Y. Li,
Acknowledgements
The authors thank to Prof. Hong Zhang, Institute of Biostatistics, School of Life Sciences, Fudan University for his helps in statistical analysis.
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These authors contributed equally to this work.