Macrophage-specific targeting of LXRs in CVD and NASH

CVD 和 NASH 中 LXR 的巨噬细胞特异性靶向

• 批准号: 10262918
• 负责人: Christopher K Glass
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262918
• 关键词: Affect; Agonist; Antiinflammatory Effect; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Collaborations; Coupled; Desmosterol; Development; Diet; Disease; Enhancers; Environmental Risk Factor; Epigenetic Process; Epitopes; Event; Family; Fatty Acids; Fatty Liver; Fibrosis; Foam Cells; Gap Junctions; Gene Expression Profile; Genes; Genetic; Hepatocyte; Homeostasis; Hypertriglyceridemia; Impairment; Individual; Insulin Resistance; Kupffer Cells; LXRalpha protein; Ligands; Liver; Liver X Receptor; Liver diseases; Longitudinal prospective study; Morbidity - disease rate; Mus; Myelogenous; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Pathway interactions; Pharmacology; Phenotype; Play; Population; Prevention; Process; Regulation; Role; Severities; Signal Transduction; Testing; United States; cell type; clinical investigation; disease phenotype; genetic approach; human subject; in vivo; liver function; macrophage; member; mimetics; monocyte; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; oxidation; peripheral blood; response; reverse cholesterol transport; transcription factor

PROJECT SUMMARY Project 1. Macrophage-specific targeting of LXRs in CVD and NASH Fatty liver diseases account for rapidly growing morbidity in the United States, where it is estimated that 80 to 100 million individuals have non-alcoholic fatty liver disease (NAFLD) and 6 to 16 million have the more severe liver disease, nonalcoholic steatohepatitis (NASH). NAFLD is a spectrum of liver conditions strongly coupled with obesity, insulin resistance, CVD, and type-2 diabetes mellitus. Long term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. The development of NAFLD and CVD is influenced by combinations of genetic and environmental factors, some of which are disease-specific and others that affect both disease processes. In this Project, we will investigate the central hypothesis that impaired function of liver X receptors in Kupffer cells in the liver and macrophages within the artery wall represent a common underlying mechanism that contributes to both NAFLD and atherosclerosis, and that this mechanism can be reversed by treatment with desmosterol mimetics. A major limitation in targeting LXRs for treatment of atherosclerosis is that most synthetic agonists cause marked hypertriglyceridemia by inducing the expression of SREBP1c in hepatocytes. Our studies of macrophage foam cells led to the finding that desmosterol, an intermediate in the cholesterol biosynthetic pathway, is the most abundant endogenous LXR agonist. Unlike conventional agonists that selectively bind to LXRs, desmosterol also binds to SCAP, thereby inhibiting processing of SREBP1 and SREBP2. Unexpectedly, we recently discovered that desmosterol and synthetic desmosterol mimetics do not activate LXR or suppress SREBP target genes in hepatocytes. In vivo studies with a synthetic desmosterol mimetic further demonstrated activation of LXR target genes in Kupffer cells but not in the liver as a whole. Our findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and hepatocytes that provide a conceptually new basis for prevention of NASH and atherosclerosis. Three Specific Aims are proposed. Specific Aim 1 will test the hypothesis that LXR activity in Kupffer cells is required for normal liver homeostasis and that Kupffer cell-specific deletion of LXRs results in exaggerated NASH and atherosclerosis. These studies will exploit new mouse models allowing Kupffer cell-specific deletion of LXRs. Specific Aim 2 will use a combination of pharmacologic and genetic approaches to test the hypothesis that selective activation of LXRs in Kupffer cells with synthetic desmosterol mimetics protects mice from NASH and atherosclerosis independent of effects of these ligands within the artery wall. Specific Aim 3, performed in collaboration with Project 4, will test the hypothesis that monocyte gene expression signatures and epigenetic landscapes in peripheral blood monocytes correlate with CVD phenotypes and the extent of fibrosis in human subjects. The proposed studies may result in qualitative advances in understanding roles of LXRs in regulation of NASH and atherosclerosis and establish the potential of desmosterol mimetics to be advanced for clinical investigation.

项目概要 项目 1. CVD 和 NASH 中 LXR 的巨噬细胞特异性靶向 在美国，脂肪肝疾病的发病率迅速上升，据估计，有 80 至 1 亿人患有非酒精性脂肪肝 (NAFLD)，其中 6 至 1600 万人患有更严重的疾病 肝脏疾病、非酒精性脂肪性肝炎（NASH）。 NAFLD 是一系列强耦合的肝脏疾病 肥胖、胰岛素抵抗、CVD 和 2 型糖尿病。长期前瞻性研究表明 NAFLD 的存在和严重程度独立预测致命和非致命的 CVD 事件。发展历程 NAFLD 和 CVD 的发生受到遗传和环境因素的综合影响，其中一些因素是 特定疾病和影响两种疾病过程的其他疾病。在这个项目中，我们将调查中央 假设肝脏中的库普弗细胞和巨噬细胞中的肝 X 受体功能受损 动脉壁代表了导致 NAFLD 和动脉粥样硬化的共同潜在机制， 并且这种机制可以通过去氨甾醇模拟物治疗来逆转。一个主要限制是 以 LXR 为靶点治疗动脉粥样硬化的原因是大多数合成激动剂会引起显着的 通过诱导肝细胞中 SREBP1c 的表达来治疗高甘油三酯血症。我们对巨噬细胞泡沫的研究 细胞导致发现去莫甾醇（胆固醇生物合成途径的中间体）是最重要的 丰富的内源性 LXR 激动剂。与选择性结合 LXR 的传统激动剂不同，去莫甾醇 还与 SCAP 结合，从而抑制 SREBP1 和 SREBP2 的加工。没想到最近我们 发现去莫甾醇和合成去莫甾醇模拟物不会激活 LXR 或抑制 SREBP 肝细胞中的靶基因。合成去莫甾醇模拟物的体内研究进一步证明 激活库普弗细胞中的 LXR 靶基因，但不激活整个肝脏中的 LXR 靶基因。我们的研究结果揭示了细胞特异性 巨噬细胞和肝细胞中 LXR 对天然和合成配体的反应存在差异，这提供了 预防 NASH 和动脉粥样硬化的新概念基础。提出了三个具体目标。 具体目标 1 将检验以下假设：库普弗细胞中的 LXR 活性是正常肝脏所必需的 体内平衡以及库普弗细胞特异性 LXR 缺失会导致 NASH 和动脉粥样硬化的加剧。 这些研究将开发新的小鼠模型，允许库普弗细胞特异性删除 LXR。具体目标2 将结合药理学和遗传学方法来检验选择性激活的假设 库普弗细胞中的 LXR 与合成去氨甾醇模拟物可保护小鼠免受 NASH 和动脉粥样硬化的影响 与动脉壁内这些配体的作用无关。具体目标 3，与 项目 4，将检验单核细胞基因表达特征和表观遗传景观的假设 外周血单核细胞与人类受试者的 CVD 表型和纤维化程度相关。这 拟议的研究可能会在理解 LXR 在 NASH 调节中的作用方面取得质的进展， 动脉粥样硬化，并建立去莫甾醇模拟物用于临床研究的潜力。