title: Advanced Glycation End Products (AGE) Potently Induce Autophagy through Activation of RAF Protein Kinase and Nuclear Factor κB (NF-κB).
abstract: Advanced glycation end products (AGE) accumulate in diabetic patients and aging people because of high amounts of three- or four-carbon sugars derived from glucose, 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 the activation of autophagy (self-eating) that might result in obesity. We detected AGE as one of the potent inducers of autophagy compared with doxorubicin and TNF. AGE-mediated autophagy is inhibited by suppression of PI3K and potentiated by the autophagosome maturation blocker bafilomycin. It increases autophagy in different cell types, and that correlates with the expression of its receptor, receptor for AGE. LC3B, the marker for autophagosomes, is shown to increase upon AGE stimulation. AGE-mediated autophagy is partially suppressed by inhibitor of NF-κB, PKC, or ERK alone and significantly in combination. AGE increases sterol regulatory element binding protein activity, which leads to an increase in lipogenesis. Although AGE-mediated lipogenesis is affected by autophagy inhibitors, AGE-mediated autophagy is not influenced by lipogenesis inhibitors, suggesting that the turnover of lipid droplets overcomes the autophagic clearance. For the first time, we provide data showing that AGE induces several cell signaling cascades, like NF-κB, PKC, ERK, and MAPK, that are involved in autophagy and simultaneously help with the accumulation of lipid droplets that are not cleared effectively by autophagy, therefore causing obesity.
authors.affiliation: From the Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India and Graduate Studies, Manipal University, Manipal, Karnataka 576104, India.
authors.forename: Neeharika
authors.initials: N
authors.lastname: Verma
authors.affiliation: From the Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India and manna@cdfd.org.in.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Manna
mesh_terms: D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000009:adverse effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012709:Serum Albumin / Q000009:adverse effects / Q000378:metabolism; D000075462:Serum Albumin, Human; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000593871:AGER protein, human; D015415:Biomarkers; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; C109748:advanced glycation end products-human serum albumin; D049452:Green Fluorescent Proteins; D048490:raf Kinases; D000075462:Serum Albumin, Human
keywords: NF-κB transcription factor; autophagy; diabetes; lipid droplet; obesity; signal transduction