Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice

Abstract

Background & AimsThe liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as non-alcoholic steatohepatitis (NASH) affects daily transcriptome rhythms in the liver remains elusive. To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. Along this, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses. Approach & ResultsComparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice revealed an almost 3h phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies revealed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared to methods without time control. ConclusionsNASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEGs detection and enhances reproducibility.