Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease

Karthickeyan Chella Krishnan, Zeyneb Kurt, Rio Barrere-Cain, Simon Sabir, Aditi Das, Raquel Floyd, Laurent Vergnes, Yuqi Zhao, Nam Che, Sarada Charugundla, Hannah Qi, Zhiqiang Zhou, Yonghong Meng, Calvin Pan, Marcus M. Seldin, Frode Norheim, Simon Hui, Karen Reue, Aldons J. Lusis*, Xia Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

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, consisting of ∼100 strains of mice with various degrees of NAFLD. We identified both tissue-specific biological processes and 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 downregulation of both Pklr and Chchd6 lowered mitochondrial respiration and led to a shift toward glycolytic metabolism, thus highlighting mitochondria dysfunction as a key mechanistic driver of NAFLD. Chella Krishnan et al. apply integrative genetics approaches to delineate “key driver” genes regulating NAFLD using multi-omics data from ∼100 mouse strains. In vivo modulation of these genes rescued animals from steatosis and insulin resistance. Follow-up bioenergetics studies highlight mitochondrial dysfunction as a key mechanistic driver of NAFLD.

Original languageEnglish
Pages (from-to)103-115.e7
Number of pages21
JournalCell Systems
Volume6
Issue number1
Early online date18 Jan 2018
DOIs
Publication statusPublished - 24 Jan 2018
Externally publishedYes

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