title: LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease.
abstract: Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-Ä¸B, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH.
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ceccarelli
authors.affiliation: Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Panera
authors.affiliation: Predictive Models for Biomedicine and Environment Unit, Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mina
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gnani
authors.affiliation: Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: De Stefanis
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Crudele
authors.affiliation: Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rychlicki
authors.affiliation: Confocal Microscopy Core Facility, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrini
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: Giovannella
authors.initials: G
authors.lastname: Bruscalupi
authors.affiliation: Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Agostinelli
authors.affiliation: Department of Radiobiology and Human Health, ENEA, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Stronati
authors.affiliation: Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.affiliation: Gradenigo Hospital, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musso
authors.affiliation: Predictive Models for Biomedicine and Environment Unit, Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Furlanello
authors.affiliation: Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.|Center for Obesity, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Svegliati-Baroni
authors.affiliation: Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C508585:IL1B protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C118738:LITAF protein, human; D008070:Lipopolysaccharides; C492727:Litaf protein, mouse; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: LITAF; LPS; NAFLD; Pathology Section; fibrosis; inflammation