Interrogating Liver Macrophage LXR Signaling in Health and Non-Alcoholic Fatty Liver Disease

研究健康和非酒精性脂肪肝中的肝脏巨噬细胞 LXR 信号传导

• 批准号: 10177866
• 负责人: Hunter R. Bennett
• 金额: $ 3.85万
• 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: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177866
• 关键词: ATAC-seq; Behavior; Bone Marrow; Cause of Death; Cell Lineage; Cell physiology; Cells; Cessation of life; ChIP-seq; Cholesterol; Cholesterol Homeostasis; Clinical; Collagen; Data; Deposition; Desmosterol; Development; Diet; Disease; Disease model; Enterobacteria phage P1 Cre recombinase; Enterocytes; Environment; Environmental Risk Factor; Fibrosis; Functional disorder; Gene Expression; Genes; Genetic Transcription; Glass; Health; Hepatic; Hepatocyte; Histologic; Histopathology; Homeostasis; Human; Individual; Infiltration; Inflammation; Inflammation Process; Inflammatory; Interleukin-1; Knock-out; Kupffer Cells; Laboratories; Lead; Ligands; Lipids; Liver; Liver Fibrosis; Liver X Receptor; Mediating; Metabolic Diseases; Modeling; Molecular; Mouse Strains; Mus; Myelogenous; Myeloid Cells; Nuclear; Nuclear Receptors; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Pilot Projects; Play; Population; Prevention; Receptor Activation; Receptor Signaling; Research; Role; Serum Markers; Signal Pathway; Signal Transduction; TLR4 gene; TNF gene; Testing; Tissues; Toll-like receptors; Transgenic Mice; Tumor-infiltrating immune cells; Western World; Work; cell type; cholesterol control; cytokine; follow-up; in vivo; inflammatory marker; insight; liver injury; macrophage; molecular targeted therapies; monocyte; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; overexpression; preclinical study; receptor binding; recruit; transcription factor; transcriptome sequencing

Project Summary: The mechanisms that drive the behavior of hepatic macrophages in homeostasis and disease are poorly understood. The liver X receptor (LXR) transcription factors are highly expressed in hepatic macrophages and hepatocytes. While in hepatocytes LXR signaling controls cholesterol metabolism, macrophage LXR signaling regulates both cholesterol metabolism and inflammation, processes that are central to the pathogenesis of non-alcoholic steatohepatitis (NASH). Activation of LXRs represses inflammation by interfering with nuclear factor κ (NFκ) activation. NFκ is a downstream target of multiple NASH signaling pathways, including toll-like-receptors, interleukin-1, and tumor-necrosis factor  The central hypothesis of this proposal is that loss of LXR signaling in liver macrophages will block LXR mediated inhibition of inflammatory signaling and worsen NASH progression. Prior research by the Glass lab has demonstrated that LXR is highly expressed in Kupffer cells (the resident macrophages of the liver) and rapidly upregulated in bone marrow derived macrophages upon entry into both healthy and NASH livers. This led to the hypothesis that loss of LXR in Kupffer cells would worsen NASH phenotypes in mice with metabolic disease via increased NFκ signaling. A pilot study was performed to examine the effect of myeloid-lineage-specific LXR deletion in NASH. In this study mice lacking myeloid LXR fed a NASH- model diet for 20 weeks demonstrated increased hepatic fibrosis, and hepatic inflammatory gene expression. However, whether this effect is due to loss of LXR in Kupffer cells or other hepatic macrophage populations present during NASH is unknown. Aim 1 will test whether loss of LXR signaling in Kupffer cells increases hepatic fibrosis and worsens NASH progression. Serum markers of inflammation, liver damage, and cholesterol metabolism and hepatic histopathology will be used to assess the effect of myeloid-specific or Kupffer cell-specific LXR knockout during NASH. ChIP-seq, ATAC-seq, and RNA-seq will be used on two novel mouse strains to mechanistically assess whether loss of LXR signaling alters inflammation in different hepatic macrophage populations during NASH. Aim 2 will test whether hepatic desmosterol is the native LXR ligand in Kupffer cells. Studies in this aim will utilize a newly developed transgenic mouse to assess the effects of hepatic desmosterol depletion on Kupffer cell transcription both at homeostasis and during NASH. If successful, these studies could identify a new myeloid specific molecular target for the treatment or prevention of NASH.

项目总结： 推动肝巨噬细胞在体内稳态和疾病中行为的机制很差 明白了。肝X受体(LXR)转录因子在肝巨噬细胞中高表达 和肝细胞。而在肝细胞中，LXR信号控制胆固醇代谢，而巨噬细胞LXR 信号调节胆固醇代谢和炎症，这两个过程是 非酒精性脂肪性肝炎的发病机制。LXRs的激活通过以下途径抑制炎症 干扰核因子κ(核因子κ)的激活。Nfκ是多个NASH信号的下游目标 包括Toll样受体、白介素1和肿瘤坏死因子在内的通路 这一提议的中心假设是，肝巨噬细胞失去lxr信号将阻断lxr。 介导性抑制炎症信号，加重NASH进展。《玻璃报》之前的研究 实验室已经证明，lxr在枯否细胞(肝脏的驻留巨噬细胞)中高表达。 并在进入健康和NASH肝脏后在骨髓来源的巨噬细胞中迅速上调。 这导致了一种假设，即枯否细胞中LxR的丢失会恶化NASH表型 通过增加核因子κ信号导致的代谢性疾病。进行了一项初步研究，以检验 NASH的髓系特异性LXR缺失。在这项研究中，缺乏髓系LXR的小鼠喂食了一种NASH- 模型饮食20周后肝纤维化加重，肝组织炎症基因表达增强 表情。然而，无论这种影响是由于库普弗细胞或其他肝巨噬细胞中lxr的丢失所致 在NASH期间出现的人群尚不清楚。 Aim 1将测试枯否细胞中LXR信号的丢失是否会增加肝纤维化和恶化 纳什进展。炎症、肝损伤、胆固醇代谢和肝脏的血清标记物 组织病理学将用于评估髓系特异性或枯否细胞特异性LXR敲除的效果 在纳什期间。ChIP-seq、atac-seq和rna-seq将用于两个新的小鼠品系 机械评估LXR信号丢失是否改变不同肝巨噬细胞的炎症 纳什期间的人口。目的2将测试肝脏促性腺激素释放激素是不是天然的LXR配体 库普弗细胞。这一目标的研究将利用新开发的转基因小鼠来评估 在稳态和非酒精性脂肪性肝病期间，肝脏的桥粒固醇耗竭对枯否细胞转录的影响。如果 如果成功，这些研究可以确定一种新的髓系特异性分子靶点用于治疗或 预防NASH。