title: Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance.
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.
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Joonseok
authors.identifier: 0000-0001-7268-5748
authors.initials: J
authors.lastname: Cho
authors.affiliation: Otsuka Maryland Medicinal Laboratories, Rockville, Maryland 20850, USA.
authors.forename: Yujian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Shi-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Aging, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Joseph
authors.affiliation: Department of Aging, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Chul
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Aging, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Srilaxmi
authors.initials: S
authors.lastname: Kalavalapalli
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Sung-Kook
authors.initials: SK
authors.lastname: Chun
authors.affiliation: Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Drake
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Aging, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Someya
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Animal Sciences, University of Florida College of Medicine, Gainesville, Florida 32611, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Wohlgemuth
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Nishanth E
authors.initials: NE
authors.lastname: Sunny
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Otsuka Maryland Medicinal Laboratories, Rockville, Maryland 20850, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiratsuchi
authors.affiliation: Department of Physiology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Terada
mesh_terms: D033742:Adenine Nucleotide Translocator 2 / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000628:therapy; D005260:Female; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009765:Obesity / Q000378:metabolism / Q000628:therapy; D020011:Protective Agents / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D033742:Adenine Nucleotide Translocator 2; D020011:Protective Agents; D001278:Atractyloside; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; C003853:carboxyatractyloside