title: Chronic hypoxia-induced alterations of key enzymes of glucose oxidative metabolism in developing mouse liver are mTOR dependent.
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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID 83209-8334, USA.
authors.forename: Vikas V
authors.initials: VV
authors.lastname: Dukhande
authors.forename: Girish C
authors.initials: GC
authors.lastname: Sharma
authors.forename: James C K
authors.initials: JC
authors.lastname: Lai
authors.forename: Reza
authors.initials: R
authors.lastname: Farahani
mesh_terms: D000818:Animals; D001835:Body Weight; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006400:Hematocrit; D000860:Hypoxia / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus