The Role of Liver X Receptors (LXRs) in the Pathogenesis of Hepatic Fibrosis

肝脏 X 受体 (LXR) 在肝纤维化发病机制中的作用

• 批准号: 8293324
• 负责人: Simon William Beaven
• 金额: $ 14.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293324
• 关键词: ADD-1 protein; Address; Affect; Agonist; Alcoholism; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Award; Biology; Bone Marrow Transplantation; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cholesterol; Chronic; Chronic Disease; Cicatrix; Collagen; Data; Development; Diabetes Mellitus; Doctor of Philosophy; Enzymes; Equilibrium; Exhibits; Fatty Acids; Fatty Liver; Fibrillar Collagen; Fibrosis; Funding; Genes; Goals; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatocyte; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Liver; Knockout Mice; Laboratories; Lead; Link; Lipids; Liver; Liver Fibrosis; Liver diseases; Mediating; Medical; Metabolic; Metabolism; Mitogens; Mus; Myofibroblast; Nuclear Receptors; Pathogenesis; Pathway interactions; Phenotype; Population; Predisposition; Production; Property; Public Health; Publications; RXR; Receptor Signaling; Regulation; Relative (related person); Repression; Research; Research Personnel; Retinoids; Role; Source; Stereotyping; Sterols; Stimulus; Testing; Training; Training Programs; Transactivation; United States National Institutes of Health; Viral hepatitis; Vitamin A; Wound Healing; base; chronic liver disease; design; fatty acid metabolism; immune function; insight; interest; lecithin-retinol acyltransferase; lipid biosynthesis; lipid metabolism; loss of function; macrophage; mutant; novel; novel therapeutics; public health relevance; receptor; receptor function; reconstitution; response; response to injury; sensor; stellate cell; ADD-1 protein; Address; Affect; Agonist; Alcoholism; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Award; Biology; Bone Marrow Transplantation; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cholesterol; Chronic; Chronic Disease; Cicatrix; Collagen; Data; Development; Diabetes Mellitus; Doctor of Philosophy; Enzymes; Equilibrium; Exhibits; Fatty Acids; Fatty Liver; Fibrillar Collagen; Fibrosis; Funding; Genes; Goals; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatocyte; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Liver; Knockout Mice; Laboratories; Lead; Link; Lipids; Liver; Liver Fibrosis; Liver diseases; Mediating; Medical; Metabolic; Metabolism; Mitogens; Mus; Myofibroblast; Nuclear Receptors; Pathogenesis; Pathway interactions; Phenotype; Population; Predisposition; Production; Property; Public Health; Publications; RXR; Receptor Signaling; Regulation; Relative (related person); Repression; Research; Research Personnel; Retinoids; Role; Source; Stereotyping; Sterols; Stimulus; Testing; Training; Training Programs; Transactivation; United States National Institutes of Health; Viral hepatitis; Vitamin A; Wound Healing; base; chronic liver disease; design; fatty acid metabolism; immune function; insight; interest; lecithin-retinol acyltransferase; lipid biosynthesis; lipid metabolism; loss of function; macrophage; mutant; novel; novel therapeutics; public health relevance; receptor; receptor function; reconstitution; response; response to injury; sensor; stellate cell

DESCRIPTION (provided by applicant): My research concerns the mechanisms by which nuclear receptors, specifically the liver X receptor (LXR), balance metabolic and inflammatory responses during the course of chronic liver injury. All forms of chronic liver disease (e.g. fatty liver, viral hepatitis, alcoholism) lead to a stereotyped wound healing response-fibrosis-that is mediated by a sub-population of liver cells known as hepatic stellate cells. These cells store 80% of the body's supply of retinoids (Vitamin A and its metabolites) but the function of retinoids in stellate cells is largely unknown. To this end, I have spent the last two years of my PhD training program with Dr. Peter Tontonoz at UCLA studying the role of cholesterol and fatty acid metabolism in hepatic stellate cells. We have discovered that global deletion of LXRs renders mice susceptible to liver fibrosis in at least two forms of liver injury. Furthermore, stellate cells from LXR null mice have a diminished pool of retinoids that correlates with a pro-inflammatory, pro-fibrotic phenotype. This suggests that cholesterol and fatty acid metabolism are important for maintaining hepatic stellate cells in a quiescent state. In Aim 1 of this proposal, we will determine the relative contribution that stellate cells make to the susceptibility of LXR null animals to develop fibrosis. Aim 2 tests the hypothesis that anti-inflammatory properties of LXRs help maintain stellate cells in a quiescent state. This aim will also test whether LXRs regulate stellate cell proliferation. Aim 3 tests the role of LXRs in the storage of vitamin A in stellate cells and the crosstalk between cholesterol, fatty acids, and retinoid metabolism. The results of these studies will define the importance of LXRs for normal stellate cell function and response to chronic liver injury. The additional training and expertise I will acquire and the data generated in the 5-year award period is expected to open up new avenues for research in stellate cell biology. It will also provide sufficient publications and data to establish myself as an independent investigator, capable of competing for R01 level funding from the NIH. PUBLIC HEALTH RELEVANCE: The research proposed here is designed to understand the relevance of metabolism to the development of liver scarring (fibrosis) that occurs in common, chronic diseases (e.g. fatty liver and diabetes, alcoholism, and viral hepatitis B and C). We are studying the body's natural cholesterol sensor, the liver X receptor (LXR), to see how it affects the activity of the specific cell in the liver that causes liver scarring to occur. This research is relevant to public health because it has the potential to identify novel targets for treating multiple types of liver diseases for which there are currently no good medical therapies.

描述（由申请人提供）： 我的研究涉及核受体，特别是肝脏X受体（LXR），在慢性肝损伤过程中平衡代谢和炎症反应的机制。各种形式的慢性肝病（例如脂肪肝，病毒肝炎，酒精中毒）导致了刻板的伤口愈合反应纤维化 - 该反应是由称为肝星状细胞的肝细胞的亚群介导的。这些细胞存储了人体80％的类视视视感素（维生素A及其代谢产物），但类维生素类动物在星状细胞中的功能在很大程度上是未知的。为此，我在UCLA的Peter Tontonoz博士的博士培训计划中度过了最后两年，研究了胆固醇和脂肪酸代谢在肝星状细胞中的作用。我们发现，LXRS的全球缺失使至少两种形式的肝损伤中易受肝纤维化的小鼠。此外，来自LXR无效小鼠的星状细胞的视网膜类动物库减少，与促炎性的促纤维化表型相关。这表明胆固醇和脂肪酸代谢对于在静止状态下保持肝星状细胞很重要。在该提案的目标1中，我们将确定星状细胞对LXR无效动物产生纤维化的敏感性的相对贡献。 AIM 2检验了以下假设：LXR的抗炎特性有助于将星状细胞保持在静止状态。该目标还将测试LXR是否调节星状细胞增殖。 AIM 3测试了LXR在维生素A在星状细胞中的储存中的作用，以及胆固醇，脂肪酸和类维生素性代谢之间的串扰。这些研究的结果将定义LXRS对正常星状细胞功能的重要性以及对慢性肝损伤的反应。我将获得的额外培训和专业知识，并预计在5年奖励期内产生的数据将为星状细胞生物学研究开放新的途径。它还将提供足够的出版物和数据来确立自己为独立研究者，能够从NIH竞争R01级资金。 公共卫生相关性： 此处提出的研究旨在了解代谢与共同发生的肝脏疤痕（纤维化）的相关性，慢性疾病（例如脂肪肝和糖尿病，酒精中毒和病毒肝炎B和C）。我们正在研究人体的天然胆固醇传感器肝X受体（LXR），以了解它如何影响肝脏在肝脏中的活性，从而导致肝脏疤痕发生。这项研究与公共卫生有关，因为它有可能识别治疗多种类型的肝病的新靶标，目前尚无良好的医疗疗法。