Disturbed Crosstalk between Cholesterol Homeostasis and Inflammation Resolution in NASH

NASH 中胆固醇稳态与炎症消退之间的干扰串扰

• 批准号: 10568478
• 负责人: Bishuang Cai
• 金额: $ 56.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568478
• 关键词: Address; Anabolism; Attenuated; Cholesterol; Cholesterol Homeostasis; Cirrhosis; Cirrhotic hepatocyte; Clinical; Clinical Trials; Data; Data Set; Disease; Docosahexaenoic Acids; FDA approved; FPR2 gene; Fibrosis; Genetic Transcription; Hepatic; Hepatocyte; High Prevalence; Human; Human Genome; Infiltration; Inflammation; Inflammatory; Interruption; LDL Cholesterol Lipoproteins; Link; Liver; Liver Fibrosis; Low Density Lipoprotein Receptor; Macrophage; Mediating; Mediator; Molecular; Morbidity - disease rate; Mus; Obesity Epidemic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Positioning Attribute; Prevalence; Primary carcinoma of the liver cells; Process; Protein Binding Domain; Public Health; Publishing; Regulation; Research Personnel; Resolution; Role; Signal Transduction; Single Nucleotide Polymorphism; Stress; Testing; Therapeutic; analog; cell type; chronic liver disease; cytokine; genome wide association study; human RNA sequencing; in vivo; innovation; insight; mortality; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; prevent; receptor; response; sensor; single-cell RNA sequencing; therapeutic target; transcriptome sequencing; uptake

Project Summary/Abstract Non-alcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide, with liver fibrosis as the most important predictor of morbidity and mortality in NASH. However, due to the major gaps in understanding the mechanisms of NASH progression, particularly fibrosis, there are no FDA-approved drugs to treat NASH and halt the progression of NASH to cirrhosis and hepatocellular carcinoma. Emerging evidence shows that excessive cholesterol accumulation in hepatocytes promotes liver fibrosis in NASH, but how hepatic cholesterol homeostasis is disrupted during NASH is not completely understood. Human genome-wide association studies (GWAS) have indicated that EH domain binding protein 1 (EHBP1) is associated with low- density lipoprotein (LDL) cholesterol levels, and single-cell RNA sequencing (scRNA-seq) of human livers has revealed that EHBP1 expression is dramatically reduced in hepatocytes from cirrhotic livers with advanced fibrosis, indicating that hepatocyte EHBP1 may play a role in liver fibrosis through modulating cholesterol metabolism. The overall objective of this proposal is to study the role and the regulation of EHBP1 in NASH. Our studies with primary human and mouse hepatocytes showed that EHBP1 deficiency enhances LDL receptor (LDLR), cellular cholesterol, and the Hippo pathway effector TAZ, a novel cholesterol sensor that can induce liver fibrosis in NASH. We further found that hepatocyte-specific silencing of EHBP1 induces liver LDLR, cholesterol, TAZ, and liver fibrosis in NASH mice. We recently published that hepatic cholesterol stabilizes TAZ, and therefore propose that hepatocyte EHBP1 reduces liver fibrosis by preventing cholesterol accumulation and suppressing TAZ in NASH (Aim 1). Our study supports a role of EHBP1 in cholesterol homeostasis to prevent liver fibrosis in NASH. However, as NASH progresses, EHBP1 expression is reduced. Surprisingly, we found that the NASH-relevant inflammatory cytokine TNFa significantly suppresses the expression of EHBP1 and PPARa, a predicted transcriptional regulator of EHBP1, in primary hepatocytes. Hence, we propose that inflammatory stress caused by TNFa disturbs cholesterol homeostasis by suppressing PPARa/EHBP1 expression in hepatocytes during NASH (Aim 2). We further found that TNFa-suppressed EHBP1 can be blocked by treatment with resolvin D1 (RvD1), a docosahexaenoic acid (DHA)–derived specialized pro-resolving mediator (SPM) that can trigger resolution of inflammation. As RvD1 is produced by macrophages, we propose that macrophage-derived RvD1 blocks TNFa-mediated EHBP1 suppression in hepatocytes and this RvD1- mediated cellular crosstalk maintains cholesterol homeostasis and prevents fibrosis in NASH (Aim 3). As the beneficial effects of SPM analogues have been tested in clinical trials for other inflammatory diseases, our study elucidating the crosstalk between inflammation resolution and cholesterol homeostasis will provide insights on the potential use of RvD1 analogues as an innovative therapeutic strategy for NASH.

项目总结/摘要 非酒精性脂肪性肝炎（NASH）已成为全球慢性肝病的主要原因， 肝纤维化是NASH发病率和死亡率的最重要预测因素。然而，由于存在重大差距， 在理解NASH进展的机制，特别是纤维化，没有FDA批准的药物 治疗NASH并阻止NASH向肝硬化和肝细胞癌的进展。新出现的证据 显示肝细胞中胆固醇过度积累促进NASH中的肝纤维化，但肝细胞中胆固醇的过度积累是如何促进NASH中的肝纤维化的？ 在NASH期间胆固醇体内平衡被破坏还不完全清楚。人类全基因组 关联研究（GWAS）表明EH结构域结合蛋白1（EHBP 1）与低血压相关 密度脂蛋白（LDL）胆固醇水平，以及人类肝脏的单细胞RNA测序（scRNA-seq）， 显示EHBP 1表达在晚期肝癌患者的肝细胞中显著降低， 提示肝细胞EHBP 1可能通过调节胆固醇在肝纤维化中发挥作用 新陈代谢.本提案的总体目标是研究EHBP 1在NASH中的作用和调节。我们 对原代人和小鼠肝细胞的研究表明，EHBP 1缺乏可增强LDL受体 （LDLR），细胞胆固醇和Hippo途径效应物TAZ，一种新的胆固醇传感器，可以诱导 NASH肝纤维化我们进一步发现，肝细胞特异性沉默EHBP 1诱导肝脏LDLR， 胆固醇、TAZ和肝纤维化。我们最近发表了肝脏胆固醇稳定TAZ， 并因此提出肝细胞EHBP 1通过防止胆固醇积累减少肝纤维化， 抑制NASH中的TAZ（目的1）。我们的研究支持EHBP 1在胆固醇稳态中的作用， NASH肝纤维化然而，随着NASH的进展，EHBP 1表达减少。令人惊讶的是，我们发现 NASH相关的炎性细胞因子TNF α显著抑制EHBP 1的表达， 原代肝细胞中预测的EHBP 1转录调节因子PPARa。因此，我们建议， TNF α引起的炎性应激通过抑制PPARa/EHBP 1来扰乱胆固醇稳态 NASH期间肝细胞中的表达（目的2）。我们进一步发现TNF α抑制的EHBP 1可以被阻断， 通过用消退素D1（RvD 1）治疗，所述消退素D1是一种二十二碳六烯酸（DHA）衍生的专门的促消退因子， 介质（SPM），可以触发炎症的解决。由于RvD 1是由巨噬细胞产生的，我们建议 巨噬细胞衍生的RvD 1阻断肝细胞中TNF α介导的EHBP 1抑制， 介导的细胞串扰维持胆固醇稳态并防止NASH中的纤维化（Aim 3）。为 SPM类似物的有益效果已经在其他炎症性疾病的临床试验中得到了检验，我们的研究 阐明炎症消退和胆固醇稳态之间的串扰将提供以下见解： RvD 1类似物作为NASH创新治疗策略的潜在用途。