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.

项目摘要/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子。然而，由于存在重大差距， 在了解NASH进展的机制，特别是纤维化方面，目前还没有FDA批准的药物 治疗NASH，阻止NASH进展为肝硬变和肝细胞癌。新出现的证据 显示NASH患者肝细胞中过度的胆固醇积聚促进了肝纤维化，但肝脏 NASH期间胆固醇稳态被破坏，目前还不完全清楚。全人类基因组 相关研究表明，EH结构域结合蛋白1(EHBP1)与低密度脂蛋白相关。 人类肝脏的密度脂蛋白(LDL)胆固醇水平和单细胞RNA测序(scRNA-seq) 研究表明，晚期肝硬变患者肝细胞中EHBP1的表达显著降低 纤维化，提示肝细胞EHBP1可能通过调节胆固醇在肝纤维化中发挥作用 新陈代谢。这项建议的总体目标是研究EHBP1在NASH中的作用和调控。我们的 对原代人和小鼠肝细胞的研究表明，EHBP1缺乏可增强低密度脂蛋白受体 低密度脂蛋白受体(LDLR)，细胞胆固醇，以及河马途径效应器TAZ，一种新型的胆固醇传感器，可以诱导 NASH的肝纤维化。我们进一步发现，EHBP1的肝细胞特异性沉默可以诱导肝脏LDLR， NASH小鼠的胆固醇、TAZ和肝纤维化。我们最近发表了肝脏胆固醇稳定TAZ的研究报告， 因此提出，肝细胞EHBP1通过防止胆固醇蓄积和 在Nash中抑制TAZ(目标1)。我们的研究支持EHBP1在胆固醇稳态中的作用，以防止 NASH的肝纤维化。然而，随着NASH的进展，EHBP1的表达减少。令人惊讶的是，我们发现 NASH相关炎性细胞因子TNFa显著抑制EHBP1和EHBP1的表达 PPARa，预测的EHBP1转录调节因子，在原代肝细胞中。因此，我们建议 肿瘤坏死因子α诱导的炎性应激通过抑制PPARa/EHBP1干扰胆固醇稳态 NASH过程中肝细胞的表达(目标2)。我们进一步发现，TNFa抑制的EHBP1可以被阻断 通过用解析素D1(RvD1)处理，二十二碳六烯酸(DHA)衍生的专业前拆分 可以触发炎症消退的介体(SPM)。由于Rvd1是由巨噬细胞产生的，我们建议 巨噬细胞来源的RvD1阻断TNFa介导的EHBP1在肝细胞中的抑制，并且这种RvD1- 在NASH中，介导的细胞串扰维持胆固醇稳态并防止纤维化(目标3)。作为 我们的研究已经在其他炎症性疾病的临床试验中测试了SPM类似物的有益效果 阐明炎症消退和胆固醇稳态之间的串扰将为 RvD1类似物作为NASH创新治疗策略的潜在用途。