权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating the role of PHD3 in lipid homeostasis

研究 PHD3 在脂质稳态中的作用

基本信息

批准号：
10430260
负责人：
MARCIA HAIGIS
金额：
$ 42.38万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430260
关键词：
5&apos -AMP-activated protein kinase Acetyl-CoA Carboxylase Acute Affect Biochemical Biological Assay Biological Markers Catabolism Cell Energetics Cell Respiration Cells Cues Dioxygenases Elements Energy Metabolism Enzymes Exercise Exercise Tolerance Family Fatty Acids Fatty acid glycerol esters Goals Health Homeostasis Human Hydroxylation Hypoxia Inducible Factor Kinetics Knockout Mice Knowledge Laboratories Link Lipids Mammals Mediating Metabolic Metabolism Mitochondria Modeling Molecular Muscle Muscle Cells Muscle Fibers Muscle function Nutrient Oxygen Pathway interactions Phosphorylation Physiological Physiology Procollagen-Proline Dioxygenase Proline Protein Family Protein Kinase Proteins Recombinants Rest Role Signal Pathway Signal Transduction Skeletal Muscle Specificity Stress Tertiary Protein Structure Testing Therapeutic Tissues addiction arm exercise capacity fatty acid metabolism fatty acid oxidation hydroxyl group hypoxia inducible factor 1 improved in vitro activity in vivo innovation insight lipid metabolism member metabolic fitness muscle metabolism muscle physiology new therapeutic target novel oxidation personalized medicine prevent response therapeutic biomarker

项目摘要

Project Summary Adaptation of cellular metabolism is crucial for maintaining tissue and whole-body homeostasis. In response to low energy or stress, cells activate AMP-activated protein kinase (AMPK) to phosphorylate acetyl-CoA carboxylase (ACC), which increases mitochondrial fatty acid oxidation (FAO) and ATP levels. However, how FAO is downregulated in energy abundance states is not fully understood. As pathways that drive fuel addiction may provide new therapeutic targets or biomarkers for personalized therapy, there is a critical need to identify pathways that regulate metabolic homeostasis. We have discovered a new nutrient-dependent signaling pathway that controls fat oxidation via a little studied member of the prolyl hydroxylase domain protein family, PHD3. PHDs are a family of -ketoglutarate dependent dioxygenases that hydroxylate substrate proline residues and have been linked to fuel switching. We find that PHD3 regulates fatty acid metabolism by hydroxylating acetyl-CoA carboxylase (ACC2), a regulator of mitochondrial FAO. In response to nutrient abundance, PHD3 activates ACC2 to inhibit catabolism of fatty acids. Since ACC2 and PHD3 are highly expressed in oxidative tissues such as skeletal muscle, this proposal will test the hypothesis that the loss of PHD3 in skeletal muscle deregulates energy homeostasis by preventing ACC2 hydroxylation, hence causing constitutive mitochondrial oxidative metabolism. This proposal will test these ideas by: 1) defining the kinetics and determining the specificity by which PHD3-mediated hydroxylation regulates ACC2, 2) defining the role of PHD3 in nutrient signaling in skeletal muscle cell energetics, and 3) testing the physiological relevance of PHD3 in muscle energy homeostasis in vivo. First, we will utilize recombinant purified PHD3 to quantify the kinetic parameters of PHD3 hydroxylation of ACC2 versus HIF1. Next we will examine the specificity of ACC2 hydroxylation by PHD1-3 (Aim 1). We will also examine the effect of PHD3 on cellular metabolism in skeletal muscle cells in response to nutrient cues. We will examine the necessity of AMPK, ACC2, and HIF1 signaling on the metabolic roles of PHD3 (Aim 2). Finally, we will examine the consequences of PHD3 activity on skeletal muscle physiology in a resting state and during acute energy challenge (Aim 3). Our overarching goal is to elucidate the molecular elements of PHD3 signaling that control cellular metabolism and to leverage these findings to ultimately develop therapeutic strategies to promote improved muscle function and metabolic fitness.

项目总结