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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: Published

See all articles by Karthickeyan Chella Krishnan

Karthickeyan Chella Krishnan

University of California, Los Angeles (UCLA) - Division of Cardiology

Zeyneb Kurt

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

Rio Barrere-Cain

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

Simon Sabir

University of California, Los Angeles (UCLA) - Department of Psychology

Aditi Das

University of California, Los Angeles (UCLA) - Department of Psychology

Raquel Floyd

University of California, Los Angeles (UCLA) - Department of Microbiology, Immunology and Molecular Genetics

Laurent Vergnes

University of California, Los Angeles (UCLA) - Department of Human Genetics

Yuqi Zhao

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

Nam Che

University of California, Los Angeles (UCLA) - Division of Cardiology

Sarada Charugundla

University of California, Los Angeles (UCLA) - Division of Cardiology

Hannah Qi

University of California, Los Angeles (UCLA) - Division of Cardiology

Zhiqiang Zhou

University of California, Los Angeles (UCLA) - Division of Cardiology

Yonghong Meng

University of California, Los Angeles (UCLA) - Division of Cardiology

Calvin Pan

University of California, Los Angeles (UCLA) - Division of Cardiology

Marcus M. Seldin

University of California, Los Angeles (UCLA) - Division of Cardiology

Frode Norheim

University of California, Los Angeles (UCLA) - Division of Cardiology

Simon Hui

University of California, Los Angeles (UCLA) - Division of Cardiology

Karen Reue

University of California, Los Angeles (UCLA) - Department of Human Genetics

Aldons J. Lusis

University of California, Los Angeles (UCLA) - Division of Cardiology

Xia Yang

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

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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 (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

Suggested Citation

Krishnan, Karthickeyan Chella and Kurt, Zeyneb and Barrere-Cain, Rio and Sabir, Simon and Das, Aditi and Floyd, Raquel and Vergnes, Laurent and Zhao, Yuqi and Che, Nam and Charugundla, Sarada and Qi, Hannah and Zhou, Zhiqiang and Meng, Yonghong and Pan, Calvin and Seldin, Marcus M. and Norheim, Frode and Hui, Simon and Reue, Karen and Lusis, Aldons J. and Yang, Xia, Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease (2018). Available at SSRN: https://ssrn.com/abstract=3155747 or http://dx.doi.org/10.2139/ssrn.3155747
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Karthickeyan Chella Krishnan

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Zeyneb Kurt

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

612 Charles E. Young Drive East
Box 957246
Los Angeles, CA 90095-7246
United States

Rio Barrere-Cain

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

612 Charles E. Young Drive East
Box 957246
Los Angeles, CA 90095-7246
United States

Simon Sabir

University of California, Los Angeles (UCLA) - Department of Psychology

1285 Franz Hall
Box 951563
Los Angeles, CA 90095-1563
United States

Aditi Das

University of California, Los Angeles (UCLA) - Department of Psychology

1285 Franz Hall
Box 951563
Los Angeles, CA 90095-1563
United States

Raquel Floyd

University of California, Los Angeles (UCLA) - Department of Microbiology, Immunology and Molecular Genetics

1602 Molecular Sciences Building
609 Charles E. Young Drive, East
Los Angeles, CA 90095
United States

Laurent Vergnes

University of California, Los Angeles (UCLA) - Department of Human Genetics

695 Charles E. Young Drive South
Los Angeles, CA 90095-7088
United States

Yuqi Zhao

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology

612 Charles E. Young Drive East
Box 957246
Los Angeles, CA 90095-7246
United States

Nam Che

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Sarada Charugundla

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Hannah Qi

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Zhiqiang Zhou

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Yonghong Meng

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Calvin Pan

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Marcus M. Seldin

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Frode Norheim

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Simon Hui

University of California, Los Angeles (UCLA) - Division of Cardiology

Los Angeles, CA 90095-6939
United States

Karen Reue

University of California, Los Angeles (UCLA) - Department of Human Genetics

695 Charles E. Young Drive South
Los Angeles, CA 90095-7088
United States

Aldons J. Lusis (Contact Author)

University of California, Los Angeles (UCLA) - Division of Cardiology ( email )

Los Angeles, CA 90095-6939
United States

Xia Yang

University of California, Los Angeles (UCLA) - Department of Integrative Biology and Physiology ( email )

612 Charles E. Young Drive East
Box 957246
Los Angeles, CA 90095-7246
United States

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