Non-alcoholic fatty liver disease (NAFLD) is a growing health problem due to the increased obesity rates, among
other factors. In its more severe stage (NASH), inflammation, hepatocellular ballooning and fibrosis are present
in the liver, which can further evolve to total liver dysfunction or even hepatocarcinoma. As a metabolic disease,
is associated to environmental factors such as diet and lifestyle conditions, which in turn can influence the
epigenetic landscape of the cells, affecting to the gene expression profile and chromatin organization. In this
study we performed ATAC-sequencing and RNA-sequencing to interrogate the chromatin status of liver biopsies
in subjects with and without NASH and its effects on RNA transcription and NASH etiology. NASH subjects
showed transcriptional downregulation for lipid and glucose metabolic pathways (e.g., ABC transporters, AMPK,
FoxO or insulin pathways). A total of 229 genes were differentially enriched (ATAC and mRNA) in NASH, which
were mainly related to lipid transport activity, nuclear receptor-binding, dicarboxylic acid transporter, and
PPARA lipid regulation. Interpolation of ATAC data with known liver enhancer regions showed differential
openness at 8 enhancers, some linked to genes involved in lipid metabolism, (i.e., FASN) and glucose homeostasis
(i.e., GCGR). In conclusion, the chromatin landscape is altered in NASH patients compared to patients without
this liver condition. This alteration might cause mRNA changes explaining, at least partially, the etiology and
pathophysiology of the disease.
