LXR-Dependent Cholesterol Sensing

LXR 依赖性胆固醇传感

基本信息

批准号：
10443955
负责人：
Ira G Schulman
金额：
$ 51.87万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443955
关键词：
Adult Affect Agonist Binding Biological Models Cardiovascular Diseases Cell model Cells Cholesterol Cholesterol Homeostasis Chronic Disease Cirrhosis Collagen Coupled Deposition Diet Dominant-Negative Mutation Enterobacteria phage P1 Cre recombinase Event Fatty Acids Fatty acid glycerol esters Fibrosis Gene Expression Genes Genetic Genetic Transcription Heart Diseases Hepatic Hepatic Stellate Cell Hepatocyte Human Immune Impairment Individual Infiltration Inflammation Inflammatory LXRalpha protein Ligands Link Liver Liver Failure Liver diseases Mus Mutation Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Pathologic Pathology Patients Pharmacology Phenotype Phenylalanine Population Primary carcinoma of the liver cells Process Risk Role Severity of illness Signal Transduction Testing Time Tissues Transcriptional Activation Transcriptional Coactivator with PDZ-Binding Motif Transcriptional Regulation Triglycerides Tryptophan Tumor-infiltrating immune cells United States cell type chronic liver disease experimental study fatty liver disease insight lipid metabolism liver inflammation mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel response selective expression sensor single-cell RNA sequencing tool

项目摘要

Project Summary: Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 25% of the adult population in the United States and approximately 25% of NAFLD patients progress to non-alcoholic steatohepatitis (NASH), characterized by liver inflammation, hepatocyte ballooning, and fibrosis. Importantly, NASH increases the risks for cirrhosis, hepatocellular carcinoma, and liver failure. The processes that trigger the progression of NAFLD to NASH or even if there is a true stepwise progression from one pathological state to the other remain to be determined. NAFLD is associated with increases in liver triglycerides and elevated rates of fatty acid synthesis. Nevertheless, since most NAFLD patients do not have NASH, it is not clear if elevated fatty acids alone are sufficient to promote inflammation and fibrosis. Cholesterol is also increased in the livers of patients with NASH and non-esterified cholesterol correlates with disease severity. We reasoned that a unique approach to unraveling the roles of cholesterol in chronic liver diseases would be to reversibly disrupt cholesterol sensing. Liver x receptor alpha (LXRα) functions as an important cholesterol sensor that regulates hepatic fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. To disrupt cholesterol sensing we have generated mouse lines that change tryptophan 441 of LXRα to phenylalanine (W441F). W441F disrupts binding of endogenous cholesterol derived LXR ligands while still allowing transcription regulation by potent synthetic agonists providing a unique tool that blocks the ability of LXRα to sense cholesterol while still allowing pharmacological control. When fed a high fat/high cholesterol diet LXRα W441F mice rapidly (within 4 weeks) develop pathologies associated with NASH. Strikingly W441F mice have decreased hepatic triglycerides but large increases in cholesterol. Therefore, NASH-like phenotypes can arise in the absence of elevated hepatic triglycerides (“cholesterol-dependent NASH”). We hypothesize that decreased LXR activity in W441F hepatocytes leads to cholesterol accumulation which serves as the initiating event promoting inflammation and fibrosis. Furthermore, we propose that elevated hepatic cholesterol promotes NASH, at least in part, via cholesterol-dependent activation of the transcriptional coactivator with PDZ binding motif (TAZ, Wwtr1). TAZ is over expressed in livers of human NASH patients and promotes inflammation and fibrosis when over expressed in mouse models. Finally, our ability to re-establish LXR activity in W441F mice using pharmacological agents provides a unique opportunity to determine if cholesterol- dependent NASH can be reversed. Taken together our proposed studies will provide new insights into the mechanisms by which elevated cholesterol levels contribute to the pathogenesis of NASH and other chronic diseases.

项目概要：据估计，美国 25% 的成年人口患有非酒精性脂肪肝 (NAFLD) 大约 25% 的 NAFLD 患者进展为非酒精性脂肪性肝炎 (NASH)，以肝脏炎症、肝细胞膨胀和纤维化为特征，重要的是，NASH 会增加风险。用于引发 NAFLD 进展的肝硬化、肝细胞癌和肝功能衰竭。 NASH 或即使存在从一种病理状态到另一种病理状态的真正逐步进展，仍有待确定确定 NAFLD 与肝脏甘油三酯的增加和脂肪酸合成率的升高有关。然而，由于大多数 NAFLD 患者没有 NASH，因此尚不清楚脂肪酸升高是否会单独导致 NASH。足以促进 NASH 患者肝脏中的炎症和纤维化。我们推断，非酯化胆固醇与疾病严重程度相关。揭示胆固醇在慢性肝病中的作用将是可逆地破坏胆固醇感应。肝脏 x 受体 α (LXRα) 作为重要的胆固醇传感器，可调节肝脂肪和转录水平上的胆固醇代谢响应胆固醇衍生物的直接结合。为了破坏胆固醇感应，我们培育了将 LXRα 的色氨酸 441 改变为苯丙氨酸 (W441F) 会破坏内源性胆固醇衍生的 LXR 配体的结合。允许通过有效的合成激动剂进行转录调节，提供了一种独特的工具来阻止 LXRα 能够感知胆固醇，同时仍允许药物控制。当喂食高脂肪/高胆固醇饮食时，LXRα W441F 小鼠迅速（4 周内）发育 W441F 小鼠的肝甘油三酯显着降低，但显着降低。因此，在没有肝脏升高的情况下，可能会出现 NASH 样表型。我们探索了 W441F 中 LXR 活性的降低。肝细胞导致胆固醇积累，这是促进胆固醇积累的起始事件此外，我们认为肝脏胆固醇升高会促进 NASH。至少部分是通过具有 PDZ 结合基序的转录辅激活因子的胆固醇依赖性激活 (TAZ、Wwtr1)。TAZ 在人类 NASH 患者的肝脏中过度表达，并促进炎症和炎症。最后，我们在 W441F 中重新建立 LXR 活性的能力。使用药物制剂的小鼠提供了一个独特的机会来确定胆固醇是否综上所述，我们提出的研究将为 NASH 提供新的见解。胆固醇水平升高导致 NASH 和其他慢性疾病发病机制的机制疾病。