title: PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alcoholic steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPARα, β/δ, and γ expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 year follow-up.
  
  
  METHODS
  Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1 year.
  
  
  RESULTS
  125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1 year of follow-up. Liver PPARα expression negatively correlated with the presence of NASH (p=0.001) and with severity of steatosis (p=0.003), ballooning (p=0.001), NASH activity score (p=0.008) and fibrosis (p=0.003). PPARα expression was positively correlated to adiponectin (R(2)=0.345, p=0.010) and inversely correlated to visceral fat (R(2)=-0.343, p<0.001), HOMA IR (R(2)=-0.411, p<0.001) and CK18 (R(2)=-0.233, p=0.012). Liver PPARβ/δ and PPARγ expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1 year, correlation of PPARα expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPARα and its target genes was significantly associated with histological improvement (p=0.008).
  
  
  CONCLUSIONS
  Human liver PPARα gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPARα and its target genes. These data might suggest that PPARα is a potential therapeutic target in NASH.
authors.affiliation: Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. Electronic address: sven.francque@uza.be.
authors.forename: Sven
authors.initials: S
authors.lastname: Francque
authors.affiliation: Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Endocrinology, Diabetes and Metabolism, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Verrijken
authors.affiliation: Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caron
authors.affiliation: Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.
authors.forename: Janne
authors.initials: J
authors.lastname: Prawitt
authors.affiliation: Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.
authors.forename: Réjane
authors.initials: R
authors.lastname: Paumelle
authors.affiliation: Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Derudas
authors.affiliation: Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.affiliation: Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Finland.
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.affiliation: Department of Medical Genetics, University of Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.affiliation: Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Endocrinology, Diabetes and Metabolism, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Mertens
authors.affiliation: Department of Abdominal Surgery, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Hubens
authors.affiliation: Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Marck
authors.affiliation: Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Michielsen
authors.affiliation: Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Endocrinology, Diabetes and Metabolism, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Gaal
authors.affiliation: Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics*; D011446:Prospective Studies; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D047493:PPAR alpha; D012313:RNA
keywords: Follow-up study; Metabolic syndrome; Non-alcoholic steatohepatitis; Pathophysiology; Peroxisome proliferator-activated receptor