Abstract
Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems.
Highlights
Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH
In the liver of obese mice we found increased levels of different classes of AGEs: CML (Fig. 1b), methylglyoxal 5-hydro-5-methylimidazolones (MG-H1) (Fig. 1c), and carboxyethyllysine (CEL) (Fig. 1d), measured with state-of-the art UPLC-MSMS, as compared to lean control mice, which were unaffected by receptor for AGEs (RAGE) deletion (Fig. 1b–d)
In this study we show in an animal model of obesity-induced NAFLD increased levels of hepatic AGEs, of RAGE expression and of Gal-3 protein amount, with no relevant modifications of other AGEs receptors and detoxification systems
Summary
Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGEdetoxifying systems. In a physiological state RAGE is expressed at low levels[11], but pathophysiological conditions, such as diabetes, chronic inflammation, or obesity, induce increased RAGE expression in different tissues, such as vasculature, adipose tissue and liver[10]. In the obese mouse model LeptrDb−/−, the genetic deletion of RAGE has been shown to reduce CML accumulation in adipose tissue, as well as circulating cytokines and adipokines, ameliorating insulin resistance[5]
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