Hepatic transcriptome profiling reveals early signatures associated with disease transition from non-alcoholic steatosis to steatohepatitis

Background and aim:Non-alcoholic fatty liver disease(NAFLD)is becoming a leading cause of chronic liver disease worldwide.The molecular events that influence disease progression from non-alcoholic fatty liver(NAFL)to aggressive non-alcoholic steatohepatitis(NASH)remain incompletely understood,leading to lack of mechanism-based targeted treatment options for NASH.This study aims to identify early signatures associated with disease progression from NAFL to NASH in mice and humans.Materials and methods:Male C57BL/6J mice were fed a high-fat,-cholesterol,and-fructose(HFCF)diet for up to 9 months.The extent of steatosis,inflammation,and fibrosis was evaluated in liver tissues.Total RNA sequencing(RNA-seq)was conducted to determine liver transcriptomic changes.Results:After being fed the HFCF diet,mice sequentially developed steatosis,early steatohepatitis,steatohepatitis with fibrosis,and eventually spontaneous liver tumor.Hepatic RNA-seq revealed that the key signatures during steatosis progression to early steatohepatitis were pathways related to extracel-lular matrix organization and immune responses such as T cell migration,arginine biosynthesis,C-type lectin receptor signaling,and cytokine-cytokine receptor interaction.Genes regulated by transcription factors forkhead box M1(FOXM1)and negative elongation factor complex member E(NELFE)were significantly altered during disease progression.This phenomenon was also observed in patients with NASH.