Regulation of Mitochondrial Biogenesis and Function by DsbA-L in the Liver

DsbA-L 在肝脏中对线粒体生物发生和功能的调节

基本信息

批准号：
9901527
负责人：
ALAN FRAZER
金额：
$ 33.98万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901527
关键词：
Affect Animal Model Binding Binding Sites Biogenesis Biology Cardiovascular Diseases Cells Chronic Cyclic GMP DNA DNA Packaging DNA biosynthesis Deacetylation Development Diet Down-Regulation Energy Metabolism Epidemic Escherichia coli Fatty Liver Glutathione S-Transferase Grant Hepatic Hepatocyte High Fat Diet Homeostasis Impairment In Vitro Inflammation Inflammatory Insulin Insulin Resistance Knock-out Knowledge Lead Light Link Lipids Liver Liver Dysfunction Liver Mitochondria Liver diseases Mediating Metabolic Metabolic Diseases Metabolic dysfunction Mitochondria Mitochondrial DNA Mitochondrial Matrix Molecular Molecular Chaperones Mus Names Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Oxidation-Reduction Oxidoreductase Pathway interactions Physiological Play Protein Acetylation Protein Deficiency Proteins Rattus Regulation Research Resistance Role Sterility Stress Structure Testing adenoviral-mediated disulfide bond enzyme activity factor A gain of function human subject in vivo knockout animal liver function mitochondrial dysfunction mtTF1 transcription factor mutant novel therapeutic intervention novel therapeutics overexpression prevent protein expression therapy resistant transcription factor

项目摘要

Abstract Mitochondria in hepatocytes play a major role in maintaining whole-body energy metabolism and normal function of the liver. Impaired mitochondrial function is closely associated with various metabolic diseases such as obesity, insulin resistance, and hepatosteatosis. However, the precise underlying mechanisms remain to be fully elucidated. Filling this major gap of knowledge will yield new information on the mechanisms underlying mitochondrial dysfunction-associated liver diseases, insulin resistance, and type 2 diabetes. Our current study focuses on the functional roles and mechanisms of action of the disulfide-bond-A oxidoreductase-like protein (DsbA-L). We recently found that DsbA-L expression is significantly reduced in the liver of obese human subjects and diet-induced obese mice. In addition, loss- and gain-of-function studies reveal that DsbA-L is a key regulator of mitochondrial integrity and function and its deficiency in the liver plays an important role in obesity-induced hepatosteatosis and metabolic dysfunction. In the current study, we will use molecular and cellular approaches as well as knockout animal models to elucidate the mechanisms regulating mitochondrial integrity and function under physiological and pathophysiological conditions. This research should shed new light on the link between obesity, mitochondrial impairment, and liver dysfunction and further our understanding of the mechanisms underlying obesity-induced insulin resistance and metabolic diseases. Thus, our proposed studies should provide valuable information on the biology of DsbA-L potentially being useful as targets of anti-obesity and anti-insulin resistance therapeutics.

抽象的肝细胞中的线粒体在维持全身能量代谢和正常状态中发挥着重要作用肝脏的功能。线粒体功能受损与多种代谢性疾病密切相关，例如如肥胖、胰岛素抵抗和肝脂肪变性。然而，其确切的潜在机制仍有待进一步研究。得到充分阐明。填补这一重大知识空白将产生有关潜在机制的新信息线粒体功能障碍相关的肝病、胰岛素抵抗和 2 型糖尿病。我们目前的研究重点是二硫键-A 的功能作用和作用机制氧化还原酶样蛋白（DsbA-L）。我们最近发现 DsbA-L 表达在肥胖人类受试者和饮食引起的肥胖小鼠的肝脏。此外，功能丧失和获得的研究揭示 DsbA-L 是线粒体完整性和功能的关键调节因子，其缺陷在肝脏中发挥作用在肥胖引起的肝脂肪变性和代谢功能障碍中发挥重要作用。在当前的研究中，我们将使用分子和细胞方法以及基因敲除动物模型来阐明调节机制生理和病理生理条件下线粒体的完整性和功能。这项研究应该为肥胖、线粒体损伤和肝功能障碍之间的联系提供了新的线索，并进一步推动我们的研究了解肥胖引起的胰岛素抵抗和代谢疾病的潜在机制。因此，我们提出的研究应该提供有关 DsbA-L 生物学的有价值的信息，可能有用抗肥胖和抗胰岛素抵抗治疗的目标。