Figure 6.

In healthy conditions, physiological levels of circulating AGEs bind to RAGE in the liver evoking a pro-inflammatory signaling. This effect is counteracted by the AGE-receptor-1 (AGE-R1) that competes with RAGE for AGEs binding and causes internalization and degradation of AGEs. The formation of endogenous AGEs is also inhibited by glyoxalase-1 (Glo-1) which detoxifies the AGE precursor methylglyoxal using reduced glutathione (GSH) as cofactor. In the liver of obese mice (RAGE+/+LeptrDb−/−) (left side of image) AGEs are produced in larger amounts and accumulate intracellularly. The expression of RAGE is greatly increased leading to activation of the NLRP3 inflammatory pathway. The presence of the alternative AGE receptor Gal-3 is enhanced, but the detoxifying systems are not induced. The excess of intracellular AGEs activates the de novo lipid synthesis by interfering with the activity of the sterol regulatory element binding protein 1c (SREBP1c), contributing to hepatosteatosis. When RAGE is deleted in the obese background (RAGE−/− LeptrDb−/−) (right side of image), expression of galectin-3 (Gal-3) is further increased and is likely to be involved in a compensative AGEs trapping from the circulation and AGEs-induced NLRP3 inflammatory signalling. The lacking of RAGE is also associated in the liver with reduced AGE-R1 expression and Glo-1 activity that fail to detoxify intracellular AGEs, thus contributing to the maintenance of high hepatic AGEs levels, and prolonging SREBP1c activation and lipids accumulation. Thus, the deletion of RAGE fails to prevent AGE accumulation, hepatosteatosis and inflammation in obese mice, due to alterations of other AGE-receptors and impairment of AGE-detoxifying system.