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.

An In Vivo Magnetic Resonance Spectroscopy Study of the Effects of Caloric and Non-Caloric Sweeteners on Liver Lipid Metabolism in Rats

“…In livers of both glucose- and fructose-fed animals, two components of the pyruvate dehydrogenase complex were upregulated (PDHA1, DLAT), suggesting increased production of acetyl-CoA [40]. This was in agreement with increased activities of glycolytic enzymes, in particular pyruvate kinase, a phenomenon also reported by others [50,51]. Decreased protein levels of several TCA cycle enzymes (ACO2, OGDH, SUCLA2, and SUCLG1), all of them catalyzing reactions downstream of citrate, suggest that TCA cycle activity might have been limited upon glucose and fructose feeding, favoring the translocation of citrate to the cytosol for lipogenesis [52].…”

TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy

“…mTOR kinase signaling regulates decisions between effector and Treg cell lineage commitment (Dang et al, 2011;Delgoffe et al, 2009;Shi et al, 2011;Zeiser et al, 2008;Zeng et al, 2013). Furthermore, the mTOR signaling pathway plays a critical role in regulating glucose uptake and energy balance, and subsequently directs cell growth and proliferation (Buller et al, 2008;Dukhande et al, 2011;Macintyre et al, 2014;Mori et al, 2009;Shi et al, 2011). Glycolysis is also regulated by HIF1a (Semenza, 2011).…”

“…Signaling in Treg Cells that Control Molecular Processes of Treg Glucose Metabolism and Suppressive Functions Recent studies have demonstrated that mTOR kinase signaling regulates Treg cell lineage commitment and differentiation (Delgoffe et al, 2009;Shi et al, 2011;Zeiser et al, 2008;Zeng et al, 2013). Furthermore, mTOR signaling plays a critical role in regu-lation of glucose uptake and energy balance and subsequently directs cell growth and proliferation (Dukhande et al, 2011;Mori et al, 2009). We therefore dissected the potential mechanistic cross-talk between the TLR8 and mTOR signaling in Treg cells.…”

Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling

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