Authors P. LEFEBVRE (1), S. FRANCQUE (2), F. LALLOYER (3), E. BAUGÉ (4), A. VERIJKEN (5), L. VAN GAAL (5), B. STAELS (3) / [1] INSERM, , France, Intitut Pasteur de Lille, [2] UZA, Edegem, Belgium, Department of Gastroenterology and Hepatology, University Hospital Antwerp, [3] Univ Lille 2, , France, Institut Pasteur de Lille, [4] Institut Pasteur, Lille, France, N/A, [5] UZA, Edegem, Belgium, Department of Endocrinology, Diabetology and Metabolism, University Hospital Antwerp,
Introduction Non Alcoholic Fatty Liver Disease (NAFLD) is associated to obesity and predisposes to liver- and extrahepatic-related morbidities such as cirrhosis, hepatocarcinoma and cardiovascular diseases. A key step in NAFLD progression is fibrosis, whereby abnormal deposition of extra-cellular matrix (ECM) components occurs in the space of Disse.
Aim
Identifying molecular mechanisms leading to increased ECM deposition, and defining molecular pathways amenable to pharmacological manipulation would be decisive in fighting NAFLD progression.
Methods A comparative analysis of liver transcriptome from NASH patients and murine models of nonalcoholic steatohepatitis (NASH) was carried out. Candidate genes whose expression was correlated to the severity of NAFLD (NASH CRN score) were selected. A gene whose expression increased in NASH/fibrosis and was normalized by the activation of hepatic peroxisome proliferator activated receptor alpha (PPARα) was identified. Its contribution to the fibrotic response was studied by gene deletion studies in mice.
Results Comparative transcriptomic studies in NASH patients and murine models of NASH or fibrosis identified a response characteristic of hepatic stellate activation. A subset of genes was identified as a potential target of the TGFb, CTGF or the PPAR pathway and involved in ECM homeostasis using data mining strategies in ChIP-Seq databases and gene ontology term enrichment. Among them, dermatopontin (Dpt) was identified as a novel contributor to the fibrotic response. Gene deletion showed decreased ECM deposition in Dpt KO mice submitted to a pro-fibrotic insult (CCl4). In various models of rodent NASH, Dpt expression was lowered by PPARα activation. Furthermore, Dpt expression was normalized by bariatric surgery in human NASH patients.
Conclusions Dpt is an important contributor to the fibrotic response and its expression is amenable to pharmacological control.