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Chronic hypoxia-induced alterations of key enzymes of glucose oxidative metabolism in developing mouse liver are mTOR dependent

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Abstract

Hypoxia is a potent regulator of gene expression and cellular energy metabolism and known to interfere with post-natal growth and development. Although hypoxia can induce adaptive changes in the developing liver, the mechanisms underlying these changes are poorly understood. To elucidate some of the adaptive changes chronic hypoxia induces in the developing liver, we studied the expression of the genes of mammalian target of rapamycin (mTOR) signaling and glucose metabolism, undertook proteomic examination with 2D gel-MS/MS of electron transport chain, and determined activities and protein expression of several key regulatory enzymes of glucose oxidative metabolism. To gain insight into the molecular mechanism underlying hypoxia-induced liver metabolic adaptation, we treated a subset of mice with rapamycin (0.5 mg/kg/day) to inhibit mTOR postnatally. Rapamycin-treated mice showed lower birth weight, lower body weight, and liver growth retardation in a pattern similar to that observed in the hypoxic mice at P30. Rapamycin treatment led to differential impact on the cytoplasmic and mitochondrial pathways of glucose metabolism. Our results suggest a decrease in mTOR activity as part of the mechanisms underlying hypoxia-induced changes in the activities of glycolytic and TCA cycle enzymes in liver. Chronic postnatal hypoxia induces mTOR-dependent differential effects on liver glycolytic and TCA cycle enzymes and as such should be studied further as they have pathophysiological implications in hepatic diseases and conditions in which hypoxia plays a role.

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Abbreviations

CS:

Citrate synthase

HK:

Hexokinase

KGDHC:

α-Ketoglutarate dehydrogenase complex

LDH:

Lactate dehydrogenase

mTOR:

Mammalian target of rapamycin

PDH:

Pyruvate dehydrogenase

PDK:

Pyruvate dehydrogenase kinase

PK:

Pyruvate kinase

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Acknowledgments

We thank Dr. Linda Mattiace and Melissa Kelly for technical assistance. This study was supported by grants from NIH/NINDS, the Gastroenterology Division, Pediatrics Department, Maria Fareri Children’s Hospital, New York Medical College and Idaho Biomedical Research Infrastructure Network (NIH NCRR BRINIP20RR016454).

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None.

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Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID, 83209-8334, USA

    Vikas V. Dukhande & James C. K. Lai

  2. Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0509, USA

    Vikas V. Dukhande

  3. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA

    Girish C. Sharma & Reza Farahani

  4. Department of Pediatrics, New York Medical College, Valhalla, NY, 10595, USA

    Girish C. Sharma & Reza Farahani

Authors
  1. Vikas V. Dukhande
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  2. Girish C. Sharma
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  3. James C. K. Lai
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  4. Reza Farahani
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Corresponding author

Correspondence to Reza Farahani.

Additional information

Vikas V. Dukhande and Girish C. Sharma contributed equally to this study.

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Dukhande, V.V., Sharma, G.C., Lai, J.C.K. et al. Chronic hypoxia-induced alterations of key enzymes of glucose oxidative metabolism in developing mouse liver are mTOR dependent. Mol Cell Biochem 357, 189–197 (2011). https://doi.org/10.1007/s11010-011-0889-z

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  • DOI: https://doi.org/10.1007/s11010-011-0889-z

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