title: Advanced glycation end products induce lipogenesis: regulation by natural xanthone through inhibition of ERK and NF-κB.
abstract: Advanced glycation end products (AGE) accumulate in diabetic patients and aged persons due to high amounts of 3- or 4-carbon derivatives of glucose. Understanding the mechanism of AGE-mediated signaling leading to these consequences, like oxidative stress, inflammation, apoptosis, etc. and its regulation would be a viable strategy to control diabetic complication and age-related diseases. We have detected the probable mechanism by which AGE increases lipogenesis, the cause of fatty liver in diabetic patients. AGE increased lipid accumulation in different cells as shown by Oil Red O staining. AGE-mediated regulation of several transcription factors was determined by gel shift assay. Antioxidants like NAC, PDTC, and vitamin C, except mangiferin, were unable to protect AGE-induced activation of SREBP and subsequent lipid accumulation. AGE increased the phosphorylation of ERK, and IKK and also DNA binding ability of SREBP, thereby its dependent gene transcription. AGE induces NF-κB which might suppress PPARγ activity, in turn reducing lipid breakdown and mobilization. Mangiferin not only inhibits AGE-mediated ROI generation that requires NF-κB activation, but also inhibits ERK and IKK activity, thereby suppression of SREBP activity and lipogenesis. Mangiferin has shown a double-edged sword effect to suppress AGE-mediated ailments by reducing ROI-mediated responses as antioxidant and inhibiting SREBP activation thereby lipogenesis, suggesting its potential efficacy against diabetes and obesity-related diseases.
authors.affiliation: Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad, India.
authors.forename: Sidhartha K
authors.initials: SK
authors.lastname: Mahali
authors.forename: Neeharika
authors.initials: N
authors.lastname: Verma
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Manna
mesh_terms: D000975:Antioxidants / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000096:biosynthesis; D015398:Signal Transduction; D044004:Xanthones / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D047495:PPAR gamma; D044004:Xanthones; C009689:xanthone