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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.

项目总结: