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Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance

Author

Listed:
  • Joonseok Cho

    (University of Florida College of Medicine)

  • Yujian Zhang

    (Otsuka Maryland Medicinal Laboratories)

  • Shi-Young Park

    (Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine)

  • Anna-Maria Joseph

    (University of Florida College of Medicine)

  • Chul Han

    (University of Florida College of Medicine)

  • Hyo-Jin Park

    (University of Florida College of Medicine)

  • Srilaxmi Kalavalapalli

    (University of Florida College of Medicine)

  • Sung-Kook Chun

    (University of Florida College of Medicine)

  • Drake Morgan

    (University of Florida College of Medicine)

  • Jae-Sung Kim

    (University of Florida College of Medicine)

  • Shinichi Someya

    (University of Florida College of Medicine)

  • Clayton E. Mathews

    (University of Florida College of Medicine)

  • Young Jae Lee

    (Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine)

  • Stephanie E. Wohlgemuth

    (University of Florida College of Medicine)

  • Nishanth E. Sunny

    (University of Florida College of Medicine)

  • Hui-Young Lee

    (Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine)

  • Cheol Soo Choi

    (Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine
    Endocrinology, Internal Medicine, Gachon University Gil Medical Center)

  • Takayuki Shiratsuchi

    (Otsuka Maryland Medicinal Laboratories)

  • S. Paul Oh

    (University of Florida College of Medicine)

  • Naohiro Terada

    (University of Florida College of Medicine)

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder in obese individuals. Adenine nucleotide translocase (ANT) exchanges ADP/ATP through the mitochondrial inner membrane, and Ant2 is the predominant isoform expressed in the liver. Here we demonstrate that targeted disruption of Ant2 in mouse liver enhances uncoupled respiration without damaging mitochondrial integrity and liver functions. Interestingly, liver specific Ant2 knockout mice are leaner and resistant to hepatic steatosis, obesity and insulin resistance under a lipogenic diet. Protection against fatty liver is partially recapitulated by the systemic administration of low-dose carboxyatractyloside, a specific inhibitor of ANT. Targeted manipulation of hepatic mitochondrial metabolism, particularly through inhibition of ANT, may represent an alternative approach in NAFLD and obesity treatment.

Suggested Citation

  • Joonseok Cho & Yujian Zhang & Shi-Young Park & Anna-Maria Joseph & Chul Han & Hyo-Jin Park & Srilaxmi Kalavalapalli & Sung-Kook Chun & Drake Morgan & Jae-Sung Kim & Shinichi Someya & Clayton E. Mathew, 2017. "Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14477
    DOI: 10.1038/ncomms14477
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    Cited by:

    1. Cecilia Patitucci & Juan Diego Hernández-Camacho & Elodie Vimont & Sonny Yde & Thomas Cokelaer & Thibault Chaze & Quentin Giai Gianetto & Mariette Matondo & Anastasia Gazi & Ivan Nemazanyy & David A. , 2023. "Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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