Nonalcoholic fatty liver disease (NAFLD) occurs in patients without significant alcohol consumption and represents a clinico-histopathological entity with histological features that resemble alcohol-induced liver injury. We have used conditional gene targeting in hepatocytes to inactivate the pVHL-E3-ubiquitin ligase, which targets Hypoxia-Inducible-Factor (HIF) for degradation under normoxia. We have discovered that increased HIF activity alters fatty acid metabolism and results in the development of non-alcoholic fatty liver disease in mice. Hypoxia-Inducible Factor-1 and -2 (HIF-1 and HIF-2) are heterodimeric basic-loop-helix transcription factors and are key mediators of cellular adaptation to diminished oxygen supply. Our findings implicate HIF signaling, in particular signaling through HIF-2, in the development of fatty liver disease. In this grant application we propose in vivo and in vitro studies that make use of conditional gene targeting technology and transgenesis to investigate the role of HIF signaling in the regulation of fatty acid uptake, synthesis, beta-oxidation and secretion. Additional in vitro studies are proposed that specifically focus on selected HIF target genes to study their role in lipid metabolism under hypoxia.
In Aim 1 we carry out functional studies in VHL mutant mice, in Aim 2 we investigate the role of HIF activation early in the development of steatosis following acute inactivation of pVHL in the adult, and Aims 3 and 4 investigate the role of HIF-2 in a wild type genetic background with a focus on HIF-2 target genes relevant for the development of steatosis. The proposed studies are not only important for our understanding of basic HIF functions in lipid metabolism, but more importantly have direct clinical relevance. We provide a direct molecular link between hypoxic injury and fatty liver development and establish a novel role for the HIF pathway in the pathogenesis of NAFLD.
This grant application examines the role of low oxygen and signaling through Hypoxia-Inducible Factor (HIF) in the regulation of hepatic fatty acid metabolism. The proposal has relevance for all patients with non-alcoholic fatty liver disease, obesity, diabetes and those that suffer from cardio-pulmonary conditions resulting in chronically low blood oxygen levels.
|Kobayashi, Hanako; Liu, Qingdu; Binns, Thomas C et al. (2016) Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin. J Clin Invest 126:1926-38|
|Kapitsinou, Pinelopi P; Rajendran, Ganeshkumar; Astleford, Lindsay et al. (2016) The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice. Mol Cell Biol 36:1584-94|
|Urrutia, Andres A; Afzal, Aqeela; Nelson, Jacob et al. (2016) Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes. Blood 128:2550-2560|
|Bryant, Andrew J; Carrick, Ryan P; McConaha, Melinda E et al. (2016) Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 310:L249-62|
|Farsijani, Navid M; Liu, Qingdu; Kobayashi, Hanako et al. (2016) Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. J Clin Invest 126:1425-37|
|Haase, Volker H (2015) A breath of fresh air for diabetic nephropathy. J Am Soc Nephrol 26:239-41|
|Kapitsinou, Pinelopi P; Haase, Volker H (2015) Molecular mechanisms of ischemic preconditioning in the kidney. Am J Physiol Renal Physiol 309:F821-34|
|Pastor-Soler, Núria M; Sutton, Timothy A; Mang, Henry E et al. (2015) Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 308:F1452-62|
|Haase, Volker H (2015) Inflammation and hypoxia in the kidney: friends or foes? Kidney Int 88:213-5|
|Koury, Mark J; Haase, Volker H (2015) Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol 11:394-410|
Showing the most recent 10 out of 23 publications