title: The TIR/BB-loop mimetic AS-1 prevents non-alcoholic steatohepatitis and hepatic insulin resistance by inhibiting NLRP3-ASC inflammasome activation.
abstract: Non-alcoholic steatohepatitis (NASH) is characterized by excessive intracellular lipid accumulation, inflammation and hepatic insulin resistance. As the incidence of NASH is increasing worldwide, there is an urgent need to find novel interventional approaches. The pro-inflammatory cytokine IL-1β, generated and released from Kupffer cells, is considered to initiate the development of NASH. AS-1, a synthetic low-molecule mimetic of myeloid differentiation primary response gene 88 (MyD88), disrupts the interaction between the IL-1 receptor and MyD88. Here, we investigated whether AS-1 could attenuate the pathogenesis of NASH with an emphasis on hepatic insulin resistance.
  
  
  
  Eight-week-old db/db mice were fed a control diet or a methionine- and choline-deficient (MCD) diet. AS-1 (50 mg·kg-1) or vehicle was administered i.p.
  
  
  
  AS-1 administration significantly ameliorated NASH as evidenced by alanine aminotransferase levels and CD68 levels in livers of MCD-fed mice. AS-1 inhibited the MCD diet-induced activation of caspase 1 and the NLRP3-ASC inflammasome, and also reduced the enhanced levels of ROS, malondialdehyde, 3-nitrotyrosine, NADPH oxidase complex and CYP reductase-associated cytochrome p450 2E1 (CYP2E1) expression in the liver. In addition, AS-1 decreased ROS, inflammasome activation and IL-1β production in free fatty acid-LPS-treated Kupffer cells. Finally, pretreatment with AS-1 significantly ameliorated gluconeogenesis and insulin desensitization induced by IL-1β, probably by blocking the interaction between MyD88 and the IL-1 receptor.
  
  
  
  Our results indicate that AS-1 can ameliorate NASH and hepatic insulin resistance and could be considered as a potential strategy for the prevention and treatment of NASH.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.|The Affiliated Kunshan Hospital of Jiangsu University, The First People's Hospital of Kunshan, Suzhou, Jiangsu, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Song
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China.
authors.forename: Man
authors.initials: M
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Linli
authors.initials: L
authors.lastname: Que
authors.affiliation: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse