Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems

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.

Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

“…Subsequent in vivo administration of RAGE siRNA in rats recapitulated these in vitro findings and delayed the development of liver fibrosis via hampered activation of NFκB . Interestingly, deletion of Ager (the gene that encodes RAGE) did not prevent development of liver steatosis, which suggests an alternate RAGE-independent mechanism of liver dysfunction mediated by MG-AGEs. , …”

“…232 Interestingly, deletion of Ager (the gene that encodes RAGE) did not prevent development of liver steatosis, which suggests an alternate RAGEindependent mechanism of liver dysfunction mediated by MG-AGEs. 226,233 MG and MG-AGEs in Immune Disorders. Recent studies have implicated MG as a potent immunosuppressor.…”

“…The impact of MG on decreased Glo1 expression is intriguing as it suggests a positive feedback loop in which elevated MG prevents its own detoxification while continuing to cause hepatic dysfunction . Excess MG leads to further MG-AGE production, and several studies have identified elevated levels of MG-AGEs in both the plasma and the serum of patients with liver disease and in obese mice. − Serum MG-AGEs and sRAGE in nondiabetic patients are associated with nonalcoholic fatty liver disease . In addition, liver steatosis and inflammation led to elevated levels of circulating MG-AGEs …”

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

“…This pathway converts glucose to fructose and is typically involved in the production of AGEs, as fructose and its metabolites are more potent nonenzymatic glycation agents than glucose, as well as in the direct induction of oxidative stress through a substantial depletion of NADPH and consequent decrease in the GSH level [ 114 ]. In turn, AGEs exert detrimental effects, either directly or via specific AGE receptors [ 115 ], and contribute significantly to oxidative stress [ 114 ]. Interestingly, although our KRIT1 +/− mouse model did not show hyperglycemia, the increased expression of key markers of enhanced glucose uptake and glycolysis/mitochondrial respiration indicated that glucose metabolism was likely to be accelerated and paralleled by perturbed and deregulated gluconeogenesis, thus leading to the same exacerbated metabolism of intracellular glucose observed during diabetes, with consequent accumulation of AGEs.…”

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) – Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

“…RAGE is expressed on multiple cell types in the liver, such as hepatocytes, stellate cells, Kupffer cells, infiltrating immune cells and vascular cells (83,84). Interestingly, in conditions in which NAFLD-type disorders occur, either through diet or genetic modification, global deletion of Ager is not protective against steatosis, inflammation or fibrosis (85,86). In contrast, mice bearing deletion of hepatocyte Ager and fed a high-AGE diet were protected from hepatic inflammation and fibrosis through suppression of the adverse effects of RAGE-induced oxidative stress (87).…”