Hypoxia-Inducible Factors in Liver Metabolism

肝脏代谢中的缺氧诱导因素

基本信息

批准号：
8446375
负责人：
Volker Hans Haase
金额：
$ 32.12万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-20 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446375
关键词：
Acute Adenoviruses Adult Albumins Alcohol consumption Alcoholic Liver Diseases Applications Grants BHLH Protein Binding Biological Process Blood Cell Line Cell Nucleus Complex Data Development Diabetes Mellitus EP300 gene Erythropoiesis Event Exploratory/Developmental Grant Family Fatty Acids Fatty Liver Fatty acid glycerol esters Funding Gene Expression Gene Targeting Gene Transfer Techniques Generations Genes Genetic Genetic Transcription Glycolysis Goals Grant Hepatic Hepatocyte Homeostasis Homologous Gene Hydroxylation Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway In Vitro Injury Iron Knock-out Knockout Mice Lead Link Liver Liver diseases Lung Mammalian Cell Mediating Mediator of activation protein Metabolic Molecular Mus Mutant Strains Mice Mutation National Institute of Diabetes and Digestive and Kidney Diseases Nucleic Acid Regulatory Sequences Obesity Oxygen Pathogenesis Patients Physiological Play Primary Cell Cultures Proline Proteins Regulation Response Elements Role SLC2A1 gene Signal Transduction Technology Testing Tetanus Helper Peptide Tetracyclines Tissues Transferrin Transgenes Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins Vascular Endothelial Growth Factors adenovirus mediated delivery adipocyte differentiation angiogenesis bHLH-PAS factor HLF cell type clinically relevant deprivation fatty acid metabolism glucose uptake hepatoma cell human ARNT protein hypoxia inducible factor 1 in vivo iron metabolism lipid metabolism liver metabolism member non-alcoholic fatty liver novel oxidation promoter protein expression public health relevance recombinase transcription factor ubiquitin-protein ligase uptake

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）发生在没有大量酒精消耗的患者中，代表具有类似于酒精诱发肝损伤的组织学特征的临床 - 依赖疗法实体。我们已经在肝细胞中使用了条件基因靶向，以使PVHL-E3-泛素连接酶灭活，该pVHL-E3-泛素连接酶靶向缺氧诱导型因子（HIF）以在正态氧下降解。我们发现，增加HIF活性会改变脂肪酸代谢，并导致小鼠非酒精性脂肪肝病的发展。低氧诱导因子-1和-2（HIF-1和HIF-2）是异二聚体基本环螺旋转录因子，是细胞适应氧气供应减少的关键介体。我们的发现暗示了HIF信号传导，特别是通过HIF-2信号传导，正在脂肪肝病的发展中。在此赠款应用中，我们提出了利用条件基因靶向技术和转基因的体内和体外研究，以研究HIF信号在调节脂肪酸摄取，合成，β-氧化和分泌方面的作用。提出了进一步的体外研究，该研究专门研究选定的HIF靶基因，以研究其在缺氧下在脂质代谢中的作用。在目标1中，我们在VHL突变小鼠中进行功能研究，在AIM 2中，我们研究了成年人PVHL急性失活后，HIF激活早期在脂肪变性中的作用，旨在3和4研究HIF-2在野生型遗传背景中的作用，重点是HIF-2靶基因与Steateass的发育有关。拟议的研究不仅对于我们对脂质代谢中基本HIF功能的理解不仅重要，而且更重要的是具有直接的临床相关性。我们在低氧损伤与脂肪肝发育之间提供了直接的分子联系，并为HIF途径在NAFLD的发病机理中建立了新的作用。