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George Hoppe, Suzy Yoon, Banu Gopalan, Rebecca Brown, Kelsey Case, Richard E Morton, Jonathan E Sears; HIF stabilization in the liver prevents ROP by secreting hepatokines capable of promoting metabolic switch in retinal endothelium. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3643.
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© ARVO (1962-2015); The Authors (2016-present)
Pharmacological stabilization of hypoxia-inducible factor (HIF) in the liver prevents hyperoxia-induced loss of the retinal capillaries in the mouse model of retinopathy of prematurity (ROP). The purpose of this study was to identify liver-derived serum proteins capable of rendering endothelial cells resistant to oxygen toxicity.
Liver-specific HIF stabilization was achieved by systemic injection of prolyl hydroxylase inhibitor DMOG. Microarray analysis of liver-derived RNA was performed using MouseRef-8 Expression BeadChip from Illumina, followed by identification of differentially expressed genes, i.e., those with FDR p value <= 0.05 and fold change >= 1.5. Expression, synthesis and secretion of candidate gene products were further evaluated in vivo (mouse liver and serum) and in vitro (hepatoma cell line Hep3B) by RT-qPCR, Western blotting and ELISA.
Gene expression profiling of liver-derived mRNA reveled that 3 top enriched functional clusters for DMOG-induced genes were related to angiogenesis (e.g., VEGFA, EPO, FLT1), glycolysis (PDK2, ENO, PGAM1, ALDOC, PFKL, GLUT1) and lipid metabolism (ANGPTL3, VLDLR, APOC). Expression of angiogenic and glycolytic genes was transient peaking at 3 hr after DMOG treatment, while the latter group, which is primarily associated with fatty acid and triglyceride transport, showed sustained induction even 24 hr later. Hepatic EPO and ANGPTL3 mRNA levels and kinetics were mirrored by their corresponding serum protein concentrations as well as by elevated serum triglycerides.
DMOG stimulates liver to secrete a unique group of proteins with documented bifunctionality, i.e., to promote cell survival and angiogenesis. Circulating liver-derived EPO and ANGPTL3 may sustain retinal endothelial cells viability in hyperoxia through switching them to aerobic glycolysis (modified Warburg effect) thereby “desensitizing” cellular metabolism to high oxygen tension.
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