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

doi:10.1038/ncomms14477

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 journal › Article › peer-review

46 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 language	English
Article number	14477
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14477
State	Published - Feb 16 2017

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Cho, J., Zhang, Y., Park, S. Y., Joseph, A. M., Han, C., Park, H. J., Kalavalapalli, S., Chun, S. K., Morgan, D., Kim, J. S., Someya, S., Mathews, C. E., Lee, Y. J., Wohlgemuth, S. E., Sunny, N. E., Lee, H. Y., Choi, C. S., Shiratsuchi, T., Oh, S. P., & Terada, N. (2017). Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nature communications, 8, Article 14477. https://doi.org/10.1038/ncomms14477

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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.",

author = "Joonseok Cho and Yujian Zhang and Park, {Shi Young} and Joseph, {Anna Maria} and Chul Han and Park, {Hyo Jin} and Srilaxmi Kalavalapalli and Chun, {Sung Kook} and Drake Morgan and Kim, {Jae Sung} and Shinichi Someya and Mathews, {Clayton E.} and Lee, {Young Jae} and Wohlgemuth, {Stephanie E.} and Sunny, {Nishanth E.} and Lee, {Hui Young} and Choi, {Cheol Soo} and Takayuki Shiratsuchi and Oh, {S. Paul} and Naohiro Terada",

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Cho, J, Zhang, Y, Park, SY, Joseph, AM, Han, C, Park, HJ, Kalavalapalli, S, Chun, SK, Morgan, D, Kim, JS, Someya, S, Mathews, CE, Lee, YJ, Wohlgemuth, SE, Sunny, NE, Lee, HY, Choi, CS, Shiratsuchi, T, Oh, SP & Terada, N 2017, 'Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance', Nature communications, vol. 8, 14477. https://doi.org/10.1038/ncomms14477

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T1 - Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance

AU - Cho, Joonseok

AU - Zhang, Yujian

AU - Park, Shi Young

AU - Joseph, Anna Maria

AU - Han, Chul

AU - Park, Hyo Jin

AU - Kalavalapalli, Srilaxmi

AU - Chun, Sung Kook

AU - Morgan, Drake

AU - Kim, Jae Sung

AU - Someya, Shinichi

AU - Mathews, Clayton E.

AU - Lee, Young Jae

AU - Wohlgemuth, Stephanie E.

AU - Sunny, Nishanth E.

AU - Lee, Hui Young

AU - Choi, Cheol Soo

AU - Shiratsuchi, Takayuki

AU - Oh, S. Paul

AU - Terada, Naohiro

PY - 2017/2/16

Y1 - 2017/2/16

N2 - 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.

AB - 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.

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SN - 2041-1723

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JO - Nature communications

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

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