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.

项目摘要 项目1。CVD和NASH中LXR的巨噬细胞特异性靶向 脂肪肝疾病是美国迅速增长的发病率，据估计有80个 1亿个人患有非酒精性脂肪肝病（NAFLD），6至1600万人患有更严重的 肝病，非酒精性脂肪性肝炎（NASH）。 NAFLD是肝条件的频谱 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CVD事件。发展 NAFLD和CVD的影响受遗传和环境因素的组合的影响，其中一些是 疾病特异性以及影响这两个疾病过程的其他人。在这个项目中，我们将调查中央 假设肝细胞中肝脏X受体在肝脏和巨噬细胞中的功能受损 动脉壁代表了一种有助于NAFLD和动脉粥样硬化的常见基本机制， 并且这种机制可以通过脱脂醇Mimetics治疗来逆转。一个主要限制 靶向LXR用于治疗动脉粥样硬化的是，大多数合成激动剂引起的标记 通过在肝细胞中诱导SREBP1C的表达来表达高甘油三酯血症。我们对巨噬细胞泡沫的研究 细胞导致发现，降霉菌是胆固醇生物合成途径中的中间体，是最多的 丰富的内源性LXR激动剂。与传统的激动剂不同，有选择地结合LXRS，Desmosterol 还结合了SCAP，从而抑制了SREBP1和SREBP2的处理。出乎意料的是，我们最近 发现脱晶蛋白和合成脱晶醇Mimetics不会激活LXR或抑制SREBP 肝细胞中的靶基因。与合成脱晶的体内研究进一步证明了 库普弗细胞中LXR靶基因的激活，但不在整个肝脏中。我们的发现揭示了细胞特定的 LXR对巨噬细胞和肝细胞中天然和合成配体的反应差异 从概念上讲，预防纳什和动脉粥样硬化的新基础。提出了三个具体目标。 特定的目标1将检验以下假设：正常肝脏需要库普弗细胞中的LXR活性 稳态和LXRS的库普夫细胞特异性缺失导致nash和动脉粥样硬化。 这些研究将利用新的小鼠模型，允许kupffer细胞特异性缺失LXR。具体目标2 将使用药理和遗传方法的组合来检验选择性激活的假设 具有合成脱晶的kupffer细胞中LXR的含量可保护小鼠免受纳什和动脉粥样硬化 独立于动脉壁内这些配体的作用。特定目标3，与 项目4将检验以下假设：单核细胞基因表达特征和表观遗传景观 外周血单核细胞与CVD表型和人类受试者的纤维化程度相关。这 拟议的研究可能会导致在理解LXR在NASH和NASH调节中的作用方面的定性进步 动脉粥样硬化并确定脱晶酚模拟物的潜力，以进行临床研究。