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

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. Mathews, Young Jae Lee, Stephanie E. Wohlgemuth, Nishanth E. Sunny, Hui-Young Lee, Cheol Soo Choi, Takayuki Shiratsuchi, S. Paul Oh and Naohiro Terada ()
Additional contact information
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
Takayuki Shiratsuchi: Otsuka Maryland Medicinal Laboratories
S. Paul Oh: University of Florida College of Medicine
Naohiro Terada: University of Florida College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14477

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