Research Papers: Pathology:

LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

Sara Ceccarelli, Nadia Panera, Marco Mina, Daniela Gnani, Cristiano De Stefanis, Annalisa Crudele, Chiara Rychlicki, Stefania Petrini, Giovannella Bruscalupi, Laura Agostinelli, Laura Stronati, Salvatore Cucchiara, Giovanni Musso, Cesare Furlanello, Gianluca Svegliati-Baroni, Valerio Nobili and Anna Alisi _

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Oncotarget. 2015; 6:41434-41452. https://doi.org/10.18632/oncotarget.5163

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Sara Ceccarelli1,*, Nadia Panera2,*, Marco Mina3, Daniela Gnani1, Cristiano De Stefanis2, Annalisa Crudele1, Chiara Rychlicki4, Stefania Petrini5, Giovannella Bruscalupi6, Laura Agostinelli4, Laura Stronati7, Salvatore Cucchiara8, Giovanni Musso9, Cesare Furlanello3, Gianluca Svegliati-Baroni4,10, Valerio Nobili2, Anna Alisi1

1Liver Research Unit, “Bambino Gesù” Children's Hospital-IRCCS, Rome, Italy

2Hepato-Metabolic Disease Unit, “Bambino Gesù” Children's Hospital-IRCCS, Rome, Italy

3Predictive Models for Biomedicine and Environment Unit, Fondazione Bruno Kessler, Trento, Italy

4Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy

5Confocal Microscopy Core Facility, “Bambino Gesù” Children's Hospital-IRCCS, Rome, Italy

6Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy

7Department of Radiobiology and Human Health, ENEA, Rome, Italy

8Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy

9Gradenigo Hospital, Turin, Italy

10Center for Obesity, Polytechnic University of Marche, Ancona, Italy

*These authors have contributed equally to this work

Correspondence to:

Anna Alisi, e-mail: [email protected]

Keywords: Pathology Section, fibrosis, LITAF, LPS, inflammation, NAFLD

Received: May 26, 2015     Accepted: September 25, 2015     Published: October 08, 2015


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.

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