Advanced glycation end products (AGE) potently induce autophagy through activation of RAF kinase and NF-KAPPA B [Molecular Bases of Disease]

November 19th, 2015 by Verma, N., Manna, S. K.

Advanced glycation end products (AGE) accumulate in diabetic patients and aging people due to high amounts of 3- or 4-carbon sugars derived from glucose and thereby causing multiple consequences including inflammation, apoptosis, obesity and age-related disorders. It is important to understand the mechanism of AGE-mediated signaling leading to activation of autophagy (self-eating) that might result in obesity. We have detected AGE as one of the potent inducers of autophagy compared to doxorubicin and TNF. AGE-mediated autophagy is inhibited by suppression of PI3 kinase and potentiated by autophagosome maturation blocker, bafilomycin. It increases autophagy in different cell types and that correlates with the expression of it receptor, RAGE. LC3B, the marker for autophagosome is shown to increase upon AGE stimulation. AGE-mediated autophagy is suppressed partially by inhibitor of NF-κB, PKC, or ERK alone and significantly in combination. AGE increases SREBP activity that leads to increase in lipogenesis. Though AGE-mediated lipogenesis is affected by autophagy inhibitor, AGE-mediated autophagy is not influenced by lipogenesis inhibitor, suggesting that the turnover of lipid droplets overcomes the autophagic clearance. For the first time, we are providing data that AGE induces several cell signaling cascades, like NF-κB, PKC, ERK, and MAPK, which are involved in autophagy and simultaneously help in accumulating lipid droplets which are not effectively cleared by autophagy, thus follows obesity.