miRNAs’ role in the rapid response of liver metabolic dysfunction during reversal of nutritional obesity
2Department of Software and Information Systems Engineering, Ben Gurion University, Israel
Using a paradigm of nutritional obesity reversal in mice, we showed that the liver rapidly reverses obesity-related steatosis and glucose overproduction (J Endocrinol 233:293;2017)- manifestation of obesity-related non-alcoholic fatty-liver disease (NAFLD). This could not be simply explained by changes in candidate metabolic genes and transcription factors mRNA levels. We therefore hypothesize that liver miRNAs rapidly respond to changes in metabolic/nutritional state, and mediate the rapid resolution of obesity-induced changes upon nutritional intervention.
We employed Nanostring liver miRNA profiling of mice fed normal-chow(NC) or HFF for 10w, or switched back after 8w-HFF to 2w-NC. In high- versus low-fat diet model, we employed NGS to detect differentially-expressed liver miRNA and mRNA.
We detected sets of differentially-expressed miRNA by Nanostring and NGS, with significant overlap between the models. Several miRNAs predicted to regulate genes involved in lipid metabolism and gluconeogenesis regulation were up-regulated by 10 weeks on HFF and decreased in the reversibility group. This rapid miRNA reversal strongly correlated with the rapid decrease in liver fat content and reversal of dys-glycemia. Furthermore, the analysis of integrated interaction networks of differentially expressed miRNAs and genes uncovered regulatory circuits that respond to dietary conditions, providing a platform to identify candidate key miRNA mediators. Finally, we demonstrate that manipulation of such differentially expressed, putative miRNA mediators, may be used to mimic obesity reversal in obese mice.
Jointly, our study provides a rational approach for developing miRNA-based therapeutics to treat obesity-related fatty liver disease and its metabolic manifestations.
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