title: Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-α-converting enzyme activity in mice.
abstract: Advanced glycation endproducts (AGEs) accumulate in patients with diabetes, yet the link between AGEs and inflammatory and fibrogenic activity in nonalcoholic steatohepatitis (NASH) has not been explored. Tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) is at the center of inflammatory processes. Because the main natural regulator of TACE activity is the tissue inhibitor of metalloproteinase 3 (Timp3), we hypothesized that AGEs induce TACE through nicotinamide adenine dinucleotide phosphate reduced oxidase 2 (NOX2); and the down-regulation of Sirtuin 1 (Sirt1)/Timp3 pathways mediate fibrogenic activity in NASH. The role of NOX2, Sirt1, Timp3, and TACE was evaluated in choline-deficient L-amino acid defined (CDAA) or Western diet (WD)-fed wild-type (WT) and NOX2(-/-) mice. To restore Timp3, mice were injected with adenovirus (Ad)-Timp3. Sirt1 and Timp3 expressions were studied in livers from NASH patients, and we found that their levels were significantly lower than in healthy controls. In WT mice on the CDAA or WD, Sirt1 and Timp3 expressions were lower, whereas production of reactive oxidative species and TACE activity significantly increased with an increase in active TNF-α production as well as induction of fibrogenic transcripts. Ad-Timp3 injection resulted in a significant decline in TACE activity, procollagen α1 (I), alpha smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-β) expression. NOX2(-/-) mice on the CDAA or WD had no significant change in Sirt1, Timp3, and TACE activity or the fibrosis markers assessed. In vitro, AGE exposure decreased Sirt1 and Timp3 in hepatic stellate cells by a NOX2-dependent pathway, and TACE was induced after exposure to AGEs.
  
  
  CONCLUSIONS
  TACE activation is central to the pathogenesis of NASH and is mediated by AGEs through NOX2 induction and down-regulation of Sirt1/Timp3 pathways.
authors.affiliation: Department of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA.
authors.forename: Joy X
authors.initials: JX
authors.lastname: Jiang
authors.forename: Xiangling
authors.initials: X
authors.lastname: Chen
authors.forename: Hiroo
authors.initials: H
authors.lastname: Fukada
authors.forename: Nobuko
authors.initials: N
authors.lastname: Serizawa
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Török
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000199:Actins / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications* / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000276:immunology; D056564:Sirtuin 1 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D017127:Glycation End Products, Advanced; D008562:Membrane Glycoproteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1