Sven Francque1, An Verrijken2, Sandrine Caron3, Janne Prawitt3, Réjane Paumelle3, Bruno Derudas3, Philippe Lefebvre3, Marja-Riitta Taskinen4, Wim Van Hul5, Ilse Mertens2, Guy Hubens6, Eric Van Marck7, Peter Michielsen8, Luc Van Gaal2, Bart Staels3. 1. 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. 2. 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. 3. Université Lille 2, INSERM U1011, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France. 4. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Finland. 5. Department of Medical Genetics, University of Antwerp, Belgium. 6. Department of Abdominal Surgery, Antwerp University Hospital, Antwerp, Belgium. 7. Department of Pathology, Antwerp University Hospital, Antwerp, Belgium. 8. 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.
Abstract
BACKGROUND & AIMS: 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). CONCLUSION: 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.
BACKGROUND & AIMS: 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 obesepatients 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). CONCLUSION: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: Joel T Haas; Luisa Vonghia; Denis A Mogilenko; An Verrijken; Olivier Molendi-Coste; Sébastien Fleury; Audrey Deprince; Artemii Nikitin; Eloïse Woitrain; Lucie Ducrocq-Geoffroy; Samuel Pic; Bruno Derudas; Hélène Dehondt; Céline Gheeraert; Luc Van Gaal; Ann Driessen; Philippe Lefebvre; Bart Staels; Sven Francque; David Dombrowicz Journal: Nat Metab Date: 2019-06-14
Authors: Sven Francque; Gyongyi Szabo; Manal F Abdelmalek; Christopher D Byrne; Kenneth Cusi; Jean-François Dufour; Michael Roden; Frank Sacks; Frank Tacke Journal: Nat Rev Gastroenterol Hepatol Date: 2020-10-22 Impact factor: 46.802