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: 8091247
• 负责人: Simon William Beaven
• 金额: $ 14.28万
• 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/8091247
• 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; 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。所有形式的慢性肝病（例如脂肪肝、病毒性肝炎、酗酒）都会导致刻板的伤口愈合反应（纤维化），这是由称为肝星状细胞的肝细胞亚群介导的。这些细胞储存了人体 80% 的类视黄醇（维生素 A 及其代谢物），但类视黄醇在星状细胞中的功能很大程度上未知。为此，我在加州大学洛杉矶分校的 Peter Tontonoz 博士的指导下度过了博士培训项目的最后两年，研究胆固醇和脂肪酸代谢在肝星状细胞中的作用。我们发现，LXR 的整体缺失使小鼠在至少两种形式的肝损伤中容易发生肝纤维化。此外，来自 LXR 缺失小鼠的星状细胞的类视黄醇库减少，这与促炎、促纤维化表型相关。这表明胆固醇和脂肪酸代谢对于维持肝星状细胞处于静止状态很重要。在本提案的目标 1 中，我们将确定星状细胞对 LXR 缺失动物发生纤维化的易感性的相对贡献。目标 2 检验了 LXR 的抗炎特性有助于维持星状细胞处于静止状态的假设。该目标还将测试 LXR 是否调节星状细胞增殖。目标 3 测试 LXR 在星状细胞中维生素 A 储存以及胆固醇、脂肪酸和类视黄醇代谢之间的串扰中的作用。这些研究的结果将明确 LXR 对正常星状细胞功能和慢性肝损伤反应的重要性。我将获得的额外培训和专业知识以及在 5 年奖励期内生成的数据预计将为星状细胞生物学研究开辟新途径。它还将提供足够的出版物和数据，使我成为一名独立研究者，有能力竞争 NIH 的 R01 级资助。 公共卫生相关性： 这里提出的研究旨在了解代谢与常见慢性疾病（例如脂肪肝和糖尿病、酗酒以及乙型和丙型病毒性肝炎）中发生的肝脏疤痕（纤维化）发展的相关性。我们正在研究人体的天然胆固醇传感器——肝脏 X 受体 (LXR)，以了解它如何影响肝脏中特定细胞的活性，从而导致肝脏疤痕的发生。这项研究与公共卫生相关，因为它有可能确定治疗多种类型肝病的新靶点，而目前尚无良好的药物疗法。