Gorrell, Kathryn H. Williams, Ana Julia Vieira de Ribeiro, Sumaiya Chowdhury, Elizabeth J. Hamson, Oliver Schilling, Emilia Prakoso, Nicholas A. Selleckchem YAP-TEAD Inhibitor 1 Shackel, Susan V. McLennan, Fiona M. Keane, Amany Zekry, Stephen Twigg Significance: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in American children and adolescents. Existent targets for NAFLD therapy include agonists of specific nuclear hormone receptors such as the farnesoid-X receptor-α (FXRα) and peroxisome-proliferator activated receptor γ (PPARγ). Whether nuclear hormone
receptor (NHR) differences play a role in disease susceptibility or treatment response is unknown. Objective: To assess whether differential expression of hepatic NHR in children relates to diagnosis or severity of nonalcoholic steatohepatitis (NASH) or NAFLD histology. Methods: Total liver mRNA was obtained from a single-center subset of children 10-19y undergoing percutaneous biopsy at end-of-treatment in the NASH Research Network TONIC trial (Lavine et al. JAMA,2011). Comparisons of NHR expression determined by high throughput quantitative PCR were made between categories of steatosis, lobular inflammation, ballooning, and NASH diagnosis. Statistical analyses used Student’s click here t-test to assess differential NHR expression by features of hepatic
histology. A hierarchical cluster analysis of the 35 NHRs was performed, with the Calinski-Harabasz index used to PLEK2 determine the # of clusters and a dendrogram used to display a graphical summary of the cluster analysis. Results: Forty children (85% Hispanic, 17% girls) with a history of biopsy-proven
NAFLD underwent analyses. At end-of-treat-ment biopsy, 19 subjects had NASH. Detectable mRNA was expressed for 35 distinct NHR. PPAR-6 demonstrated higher expression for diagnosis of NASH v “not NASH” (p=0.02), for stage of fibrosis (2-4 v 0-1, p=0.04), lobular inflammation (2-3 v 1-2, p=0.01) and ballooning (1-2 v 0, p=0.08). Reti-noic acid receptor-p (RARp) demonstrated significantly higher expression for diagnosis of NASH v “not NASH” (p=0.02) and for steatosis (2-3 v 1-2, p=0.01). Expression of PPARγ and PPARγ2 demonstrated significant differences in lobular inflammation (0-1 v. 2-3, p=0.01 and p<0.001, respectively). Higher FXRα expression levels associated with higher steatosis score (p=0.01). Conclusions: Expression differences in specific NHR known to be pleiotropic transactivators regulating lipid metabolism and energy homeostasis, bile acid metabolism, and basal metabolic functions are associated with the histologic severity of NAFLD including the diagnosis of NASH. If protein levels for these effectors are found to relate to these expression profiles, these receptors identify novel therapeutic targets. Disclosures: Joel E. Lavine – Consulting: Merck, Crosscare, Gilead, Takeda Millenium; Grant/ Research Support: Janssen Jeffrey B. Schwimmer – Speaking and Teaching: Daiichi Sankyo, Inc. Cynthia A.