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

• Published in: Nature communications 2017-02, Vol.8 (1), p.14477-14477, Article 14477
• Main Authors: Cho, Joonseok, Zhang, Yujian, Park, Shi-Young, Joseph, Anna-Maria, Han, Chul, Park, Hyo-Jin, Kalavalapalli, Srilaxmi, Chun, Sung-Kook, Morgan, Drake, Kim, Jae-Sung, Someya, Shinichi, Mathews, Clayton E., Lee, Young Jae, Wohlgemuth, Stephanie E., Sunny, Nishanth E., Lee, Hui-Young, Choi, Cheol Soo, Shiratsuchi, Takayuki, Oh, S. Paul, Terada, Naohiro
• Format: Article
• Language: English
• Subjects: 13/51; 14/28; 14/69; 38/39; 38/77; 42; 42/41; 631/80/642/333/1465; 631/92/577; 692/4020/4021/1607/2750; Adenine Nucleotide Translocator 2 - genetics; Adenine Nucleotide Translocator 2 - metabolism; Adenosine Triphosphate - metabolism; Animals; Atractyloside - analogs & derivatives; Diet, High-Fat; Disease Models, Animal; Fatty Liver - metabolism; Fatty Liver - therapy; Female; Glucose Clamp Technique; Homeostasis; Humanities and Social Sciences; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver - metabolism; Liver - pathology; Liver diseases; Male; Medical schools; Medicine; Metabolism; Mice; Mice, Knockout; Microscopy; Mitochondria; Mitochondria, Liver - metabolism; Mitochondrial Membranes - metabolism; multidisciplinary; NMR; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - therapy; Nuclear magnetic resonance; Obesity; Obesity - metabolism; Obesity - therapy; Pathology; Protective Agents - metabolism; Proteins; Pyruvic Acid - metabolism; Respiration; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14477

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. Adenine nucleotide translocase (ANT) 2 promotes ADP/ATP exchange across the mitochondrial inner membrane. Cho et al . show that liver specific Ant2 deletion increases uncoupled respiration and protects mice against fatty liver and obesity-induced insulin resistance.