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, Naohiro Terada

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish
Article number14477
JournalNature communications
Volume8
DOIs
StatePublished - Feb 16 2017

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