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Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.
- Source :
-
Journal of Clinical Investigation . Apr2007, Vol. 117 Issue 4, p1068-1077. 10p. 1 Black and White Photograph, 6 Graphs. - Publication Year :
- 2007
-
Abstract
- Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1alpha and/or Hif-2alpha (Epas1) in hepatocytes. We have previously shown that inactivation of the von Hippel-Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia independent of Hif-1alpha. Here we show that conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2alpha but not Hif-1alpha and that the hypoxic induction of liver Epo in anemic adults was Hif-2alpha dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1alpha dependent, we provide genetic evidence that HIF-1 and HIF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIF-2 in the liver. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ERYTHROPOIESIS
*ERYTHROPOIETIN
*GLYCOPROTEINS
*HYPOXEMIA
*LIVER cells
*POLYCYTHEMIA
*EPITHELIAL cells
*LIVER physiology
*ANIMAL experimentation
*BIOLOGICAL models
*BONE marrow diseases
*COMPARATIVE studies
*GENES
*RESEARCH methodology
*MEDICAL cooperation
*MICE
*PROTEINS
*RESEARCH
*RESEARCH funding
*EVALUATION research
*VON Hippel-Lindau disease
*CELL physiology
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 117
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 24739872
- Full Text :
- https://doi.org/10.1172/JCI30117