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Nat Commun. 2017 Feb 16;8:14477. doi: 10.1038/ncomms14477.

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

Author information

1
Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
2
Otsuka Maryland Medicinal Laboratories, Rockville, Maryland 20850, USA.
3
Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
4
Department of Aging, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
5
Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
6
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
7
Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
8
Department of Animal Sciences, University of Florida College of Medicine, Gainesville, Florida 32611, USA.
9
Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, Korea.
10
Department of Physiology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.

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.

PMID:
28205519
PMCID:
PMC5316896
DOI:
10.1038/ncomms14477
[Indexed for MEDLINE]
Free PMC Article

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