From nutrition to metabolic and neurovascular dysfunction : is RAGE-TXNIP axis the key ?

Orateur : Lorena PERRONE

Recent evidences demonstrate that dietary Advanced Glycation Endproducts (AGEs) play a central role in promoting several age-related diseases, such as type 2 diabetes, cardiovascular diseases, obesity, metabolic syndrome, and also cognitive impairment. These diseases present a major health problem and heavy economic burden in industrialized countries. The nutritional behavior exerts long resting effects. Thus, it is essential to validate the role of dietary AGEs in order to set up preventive strategies. Several studies demonstrated that high dietary AGEs intake correlates with age-related diseases. We demonstrated that enhanced AGEs dietary content assessed 20 years before Alzheimer diagnosis strongly correlates with AD incidence in several populations following different dietary behavior. However, the molecular pathways induced by dietary AGEs are not fully unveiled. Dietary AGEs induce the aberrant glycosylation of proteins and other macromolecules, altering their function. Dietary AGEs induces also the activation of the Receptor of AGEs (RAGE), which promotes inflammation and oxidative stress. We recently demonstrated that AGEs-induced RAGE activation leads to the overexpression of Thioredoxin interacting protein (TXNIP). TXNIP is the inhibitor of the Thioredxin (Trx) ROS scavenger system. In addition, TXNIP promotes neurovascular dysfunction, activates the NLRP-3 inflammasome and the innate immunity, and is implicated in amino-acids, glucose and lipid metabolism. Interestingly, in the hypothalamus TXNIP plays a central role in regulating the food-intake. These data are strongly suggesting that dietary AGEs may produce a chronic feedback loop by activating TXNIP, leading to altered food intake, glucose and amino-acid metabolism, neurovascular dysfunction, and the activation of the innate immunity. We also demonstrated that TXNIP induces epigenetic alterations of the gene expression, providing an explanation of the long-resting effects induced by dietary AGEs. In summary, our data demonstrates that AGEs induces chronic effects by activating TXNIP, which plays a central role in modulating the metabolism at the body as well as the cellular level. The signaling pathways activated by TXNIP will be illustrated.

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