PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis

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 PPAR alpha, beta/delta, and gamma 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 PPAR alpha 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). PPAR alpha 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 PPAR beta/delta and PPAR gamma expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1 year, correlation of PPAR alpha expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPAR alpha and its target genes was significantly associated with histological improvement (p = 0.008). Conclusion: Human liver PPAR alpha 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 PPAR alpha and its target genes. These data might suggest that PPAR alpha is a potential therapeutic target in NASH. (C) 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.