Molecular mechanisms of fatty liver disease: role of the protein DBC1

脂肪肝疾病的分子机制：蛋白质 DBC1 的作用

基本信息

批准号：
8500250
负责人：
Eduardo N Chini
金额：
$ 25.01万
依托单位：
MAYO CLINIC ROCHESTER
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：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500250
关键词：
Accounting Address Age American Animal Model Binding Biochemical Caloric Restriction Cardiovascular system Cell model Cessation of life Data Deacetylase Developed Countries Developing Countries Development Diet Disease Dissociation Enzymes Fatty Liver Fatty acid glycerol esters Future Genes Health Hepatic Investigation KIAA1967 gene Knock-out Knockout Mice Laboratories Lead Light Liver Liver diseases Longevity Malignant Neoplasms Mediating Metabolic Metabolic syndrome Metabolism Molecular Molecular Biology Techniques Mus Organism Pathway interactions Patients Physiological Play Process Proteins Public Health Regulation Reporting Resistance Role Starvation Testing Therapeutic Wild Animals adenylate kinase base fatty acid oxidation in vitro Assay in vivo inhibitor/antagonist lipid biosynthesis lipid metabolism meetings member mortality non-alcoholic fatty liver novel oxidation trend

项目摘要

DESCRIPTION (provided by applicant): Recently the American Association for the Study of Liver Disease stated that "...Overall, patients with non-alcoholic fatty liver disease (NAFLD) have reduced long-term survival, with liver disease accounting for about 10% of overall mortality.... Clearly it appears that NAFLD will become a more prevalent problem in coming years..." This indicates that NAFLD will become a major public health issue in the near future. However, to date, therapeutic options for this disease are limited. In this regard, it is imperative to further understand the molecular mechanisms that modulate the development of liver steatosis. We observed that the protein Deleted in Breast Cancer 1 (DBC1) plays a crucial role in the development of experimental liver steatosis. In particular we found that mice knocked out for DBC1 are resistant to high fat diet-induced liver steatosis, while the systemic metabolic syndrome was not ameliorated. This suggests that DBC1 controls intrinsic hepatic mechanisms involved in the development of liver steatosis. To date very little is known about the physiological and biochemical roles of DBC1, however recent studies indicate that DBC1 binds and inhibits the enzyme SIRT1. SIRT1 is a NAD-dependent deacetylase that controls metabolism, ageing and longevity. In fact, it has been proposed that SIRT1 is a metabolic master switch. Pharmacological activation of SIRT1 protects against liver steatosis, at least in part, via stimulation of the AMP kinase (AMPK) that subsequently decreases lipogenesis and increases fatty acid oxidation. Although the metabolic actions of SIRT1 are the subject of intense investigation; much less is known about regulation of SIRT1. In fact, the mechanisms that modulate SIRT1 expression and activity remain elusive. In this regard, the characterization of DBC1 as an endogenous inhibitor of SIRT1, and the determination of the mechanisms that regulate the DBC1-SIRT1 interaction are of extreme importance. It is possible that modulation of DBC1-SIRT1 interaction plays a key role in the regulation of SIRT1 function during different metabolic conditions, including diet-induced steatosis. An increase in interaction between DBC1 and SIRT1 may also provide the molecular basis for the decrease in SIRT1 activity reported in animal models of diet-induced liver steatosis. Thus, our Central Hypothesis is that DBC1 plays a crucial role in the development of liver steatosis by direct binding and inhibiting SIRT1, with the subsequent modulation of downstream effects of SIRT1 on hepatic lipogenesis and 2-oxidation via AMPK. To test this hypothesis, the following specific aims will be addressed: Aim 1. Study the role of SIRT1 in DBC1-mediated regulation of liver steatosis. Aim 2. Characterize the role of DBC1 in the regulation of SIRT1 activity during different caloric loads and determine the molecular mechanisms that regulate the DBC1-SIRT1 interaction. Aim 3. Determine the biochemical mechanisms, downstream from SIRT1, by which DBC1 regulates the development of liver steatosis: role of AMPK. Collectively, these studies will lead to an in depth and extremely novel understanding of the physiological roles of DBC1 as a regulator of SIRT1, liver fat metabolism and hepatic steatosis.

描述（申请人提供）：最近美国肝病研究协会表示“……总体而言，非酒精性脂肪肝病（NAFLD）患者的长期生存率降低，其中肝病患者约占 10%。占总死亡率的百分比......显然，NAFLD 在未来几年将成为一个更加普遍的问题......”这表明 NAFLD 将在不久的将来成为一个主要的公共卫生问题。然而，迄今为止，这种疾病的治疗选择是有限的。在这方面，有必要进一步了解调节肝脏脂肪变性发展的分子机制。我们观察到乳腺癌删除蛋白 1 (DBC1) 在实验性肝脂肪变性的发展中起着至关重要的作用。特别是，我们发现 DBC1 基因敲除的小鼠对高脂肪饮食诱导的肝脏脂肪变性具有抵抗力，而全身代谢综合征并未得到改善。这表明 DBC1 控制参与肝脏脂肪变性发展的内在肝脏机制。迄今为止，人们对 DBC1 的生理和生化作用知之甚少，但最近的研究表明，DBC1 结合并抑制 SIRT1 酶。 SIRT1 是一种 NAD 依赖性脱乙酰酶，可控制新陈代谢、衰老和寿命。事实上，有人提出SIRT1是代谢总开关。 SIRT1 的药理学激活至少部分通过刺激 AMP 激酶 (AMPK) 来防止肝脏脂肪变性，从而减少脂肪生成并增加脂肪酸氧化。尽管 SIRT1 的代谢作用是深入研究的主题；人们对 SIRT1 的调控知之甚少。事实上，调节 SIRT1 表达和活性的机制仍然难以捉摸。在这方面，DBC1 作为 SIRT1 内源性抑制剂的表征以及调节 DBC1-SIRT1 相互作用的机制的确定极其重要。 DBC1-SIRT1 相互作用的调节可能在不同代谢条件（包括饮食诱导的脂肪变性）期间 SIRT1 功能的调节中发挥关键作用。 DBC1 和 SIRT1 之间相互作用的增加也可能为饮食诱导的肝脂肪变性动物模型中报道的 SIRT1 活性降低提供分子基础。因此，我们的中心假设是，DBC1 通过直接结合和抑制 SIRT1，随后通过 AMPK 调节 SIRT1 对肝脂肪生成和 2-氧化的下游影响，在肝脏脂肪变性的发展中发挥至关重要的作用。为了检验这一假设，将解决以下具体目标：目标 1. 研究 SIRT1 在 DBC1 介导的肝脏脂肪变性调节中的作用。目标 2. 表征不同热量负荷期间 DBC1 在调节 SIRT1 活性中的作用，并确定调节 DBC1-SIRT1 相互作用的分子机制。目标 3. 确定 SIRT1 下游 DBC1 调节肝脏脂肪变性发展的生化机制：AMPK 的作用。总的来说，这些研究将带来对 DBC1 作为 SIRT1、肝脏脂肪代谢和肝脂肪变性调节剂的生理作用的深入且极其新颖的理解。