Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease
50 Pages Posted: 11 Apr 2018 Sneak Peek Status: PublishedMore...
The etiology of non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, is poorly understood. To understand the causal mechanisms underlying NAFLD, we conducted a multi-omics, multi-tissue integrative study using the Hybrid Mouse Diversity Panel (HMDP), consisting of ~100 strains of mice with various degrees of NAFLD. We identified both tissue-specific biological processes as well as processes that were shared between adipose and liver tissues. We then used gene network modeling to predict candidate regulatory genes of these NAFLD processes, including Fasn, Thrsp, Pklr, and Chchd6. In vivo knockdown experiments of the candidate genes improved both steatosis and insulin resistance. Further in vitro testing demonstrated that down regulation of both Pklr and Chchd6 lowered mitochondrial respiration and led to a shift towards glycolytic metabolism, thus highlighting mitochondria dysfunction as a key mechanistic driver of NAFLD.
Keywords: Non-alcoholic fatty liver disease; multi-omics integration; network modeling; key drivers; mitochondrial dysfunction; oxidative phosphorylation; glycolysis
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