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Abstract
Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the regulation of metabolism, oxygen delivery and cell survival. Although the involvement of HIFs in the regulation of carbohydrate metabolism and the switch to anaerobic glycolysis under hypoxia is well established, their role in the control of lipid anabolism and catabolism remains still relatively obscure. Recent evidence indicates that many aspects of lipid metabolism are modified during hypoxia or in tumor cells in a HIF-dependent manner, contributing significantly to the pathogenesis and/or progression of cancer and metabolic disorders. However, direct transcriptional regulation by HIFs has been only demonstrated in relatively few cases, leaving open the exact and isoform-specific mechanisms that underlie HIF-dependency. This review summarizes the evidence for both direct and indirect roles of HIFs in the regulation of genes involved in lipid metabolism as well as the involvement of HIFs in various diseases as demonstrated by studies with transgenic animal models.
Highlights
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, BIOPOLIS, 41500 Larissa, Greece; Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H4A 3T2, Canada
KO cannot be necessarily attributed to hypoxia-inducible factors (HIFs) activity, since PHDs may have additional substrates or partners [108], pulmonary hypertension has been long known to be linked to HIF activation, since exposure to chronic hypoxia can cause pulmonary arterial smooth muscle cell proliferation, migration and hypertrophy leading to pulmonary vascular remodeling and eventually pulmonary hypertension [109]
Recent information gathered from investigations in cell lines, animals and patient biopsy samples signify the importance of hypoxia and HIF activation in the regulation of lipid metabolism, and their contribution to the development and progression of cancer and other pathological conditions associated with the accumulation of lipids in various types of cells and organs
Summary
Direct phosphorylation by several kinases is important for HIF-1α regulation and is extensively studied (reviewed in [25]) (Figure 2). CRM1 binding and increasing phosphorylates HIF-1α at sites adjacent to an atypical hydrophobic nuclear export signal (NES), the nuclear concentration activity of increasing. Inhibition of ERK-mediated phosphorylation of HIF-1α tips the balance in favor of nuclear. After with treatment of human bronchial smooth muscle Activating cells with be inhibited by interaction of HIF-1α. The crosstalk between the signaling pathways, that result to modification and regulation of the HIF-α isoforms, with those controlling metabolic homeostasis may define the exact role of HIFs in the metabolic adaptation of cells to hypoxia.
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