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Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease.
Chella Krishnan, Karthickeyan; Kurt, Zeyneb; Barrere-Cain, Rio; Sabir, Simon; Das, Aditi; Floyd, Raquel; Vergnes, Laurent; Zhao, Yuqi; Che, Nam; Charugundla, Sarada; Qi, Hannah; Zhou, Zhiqiang; Meng, Yonghong; Pan, Calvin; Seldin, Marcus M; Norheim, Frode; Hui, Simon; Reue, Karen; Lusis, Aldons J; Yang, Xia.
Affiliation
  • Chella Krishnan K; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Kurt Z; Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
  • Barrere-Cain R; Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
  • Sabir S; Department of Psychology, College of Letters and Science, University of California, Los Angeles, CA, USA.
  • Das A; Department of Psychology, College of Letters and Science, University of California, Los Angeles, CA, USA.
  • Floyd R; Department of Microbiology, Immunology and Molecular Genetics, College of Letters and Science, University of California, Los Angeles, CA, USA.
  • Vergnes L; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Zhao Y; Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
  • Che N; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Charugundla S; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Qi H; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Zhou Z; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Meng Y; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Pan C; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Seldin MM; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Norheim F; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Hui S; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Reue K; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Lusis AJ; Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, College of Letters and Science, University of California, Los Angeles, CA, USA; Department of Human Genetics,
  • Yang X; Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA. Electronic address: xyang123@ucla.edu.
Cell Syst ; 6(1): 103-115.e7, 2018 Jan 24.
Article in En | MEDLINE | ID: mdl-29361464
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Non-alcoholic Fatty Liver Disease Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Cell Syst Year: 2018 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Non-alcoholic Fatty Liver Disease Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Cell Syst Year: 2018 Document type: Article Affiliation country: United States