title: Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation.
abstract: OBJECTIVE
  Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation.
  
  
  RESULTS
  Rats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and pro-inflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructose-exposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers.
  
  
  CONCLUSIONS
  This study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway.
authors.affiliation: 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing, People's Republic of China .
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhang
authors.forename: Xu-Yang
authors.initials: XY
authors.lastname: Chen
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Hu
authors.forename: Ming-Xing
authors.initials: MX
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Jin
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Kang
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Li
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Pan
authors.forename: Jun-Jian
authors.initials: JJ
authors.lastname: Huang
authors.forename: Ling-Dong
authors.initials: LD
authors.lastname: Kong
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D017382:Reactive Oxygen Species; C493796:TXNIP protein, rat; D005632:Fructose; D000493:Allopurinol; D011794:Quercetin