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LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease.
- Source :
-
Oncotarget [Oncotarget] 2015 Dec 08; Vol. 6 (39), pp. 41434-52. - Publication Year :
- 2015
-
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-ĸB, 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.
- Subjects :
- Animals
Binding Sites
Cell Line
Cytokines genetics
DNA-Binding Proteins
Female
Hepatic Stellate Cells drug effects
Hepatic Stellate Cells immunology
Hepatic Stellate Cells pathology
Humans
Interleukin-1beta genetics
Interleukin-1beta metabolism
Lipopolysaccharides pharmacology
Liver drug effects
Liver immunology
Liver pathology
Liver Cirrhosis drug therapy
Liver Cirrhosis genetics
Liver Cirrhosis immunology
Liver Cirrhosis pathology
Male
Mice
Mice, Inbred BALB C
Non-alcoholic Fatty Liver Disease drug therapy
Non-alcoholic Fatty Liver Disease genetics
Non-alcoholic Fatty Liver Disease immunology
Non-alcoholic Fatty Liver Disease pathology
Nuclear Proteins genetics
Phenotype
Promoter Regions, Genetic
Protein Kinase Inhibitors pharmacology
RNA Interference
Signal Transduction
Time Factors
Transcription Factors genetics
Transcription, Genetic
Transfection
Up-Regulation
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases metabolism
Cytokines metabolism
Hepatic Stellate Cells metabolism
Inflammation Mediators metabolism
Liver metabolism
Liver Cirrhosis metabolism
Non-alcoholic Fatty Liver Disease metabolism
Nuclear Proteins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 39
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26573228
- Full Text :
- https://doi.org/10.18632/oncotarget.5163