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.

项目概要/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 发病率和死亡率最重要的预测因子。但由于存在较大差距 在了解 NASH 进展（尤其是纤维化）的机制方面，尚无 FDA 批准的药物 治疗 NASH 并阻止 NASH 进展为肝硬化和肝细胞癌。新出现的证据 表明肝细胞中过多的胆固醇积累会促进 NASH 中的肝纤维化，但肝脏如何 NASH 期间胆固醇稳态被破坏的情况尚不完全清楚。人类全基因组 关联研究 (GWAS) 表明 EH 结构域结合蛋白 1 (EHBP1) 与低 密度脂蛋白 (LDL) 胆固醇水平和人类肝脏的单细胞 RNA 测序 (scRNA-seq) 已 研究表明，晚期肝硬化肝细胞中 EHBP1 的表达显着降低。 纤维化，表明肝细胞EHBP1可能通过调节胆固醇在肝纤维化中发挥作用 代谢。本提案的总体目标是研究 EHBP1 在 NASH 中的作用和调控。我们的 对人类和小鼠原代肝细胞的研究表明，EHBP1 缺陷会增强 LDL 受体 (LDLR)、细胞胆固醇和 Hippo 通路效应器 TAZ（一种新型胆固醇传感器，可诱导 NASH 中的肝纤维化。我们进一步发现肝细胞特异性沉默 EHBP1 会诱导肝脏 LDLR， NASH 小鼠中的胆固醇、TAZ 和肝纤维化。我们最近发表了肝脏胆固醇可以稳定 TAZ， 因此提出肝细胞EHBP1通过防止胆固醇积累和减少肝纤维化 抑制 NASH 中的 TAZ（目标 1）。我们的研究支持 EHBP1 在胆固醇稳态中的作用，以预防 NASH 中的肝纤维化。然而，随着 NASH 的进展，EHBP1 表达减少。令人惊讶的是，我们发现 NASH 相关炎症细胞因子 TNFa 显着抑制 EHBP1 的表达 PPARa，原代肝细胞中 EHBP1 的预测转录调节因子。因此，我们建议 TNFa 引起的炎症应激通过抑制 PPARa/EHBP1 扰乱胆固醇稳态 NASH 期间肝细胞中的表达（目标 2）。我们进一步发现TNFa抑制的EHBP1可以被阻断 通过使用 resolvin D1 (RvD1) 进行治疗，这是一种二十二碳六烯酸 (DHA) 衍生的专门的促分解蛋白 可以触发炎症消退的介质（SPM）。由于 RvD1 由巨噬细胞产生，我们建议 巨噬细胞衍生的 RvD1 阻断肝细胞中 TNFa 介导的 EHBP1 抑制，并且该 RvD1- 介导的细胞串扰可维持胆固醇稳态并防止 NASH 中的纤维化（目标 3）。作为 我们的研究已在其他炎症性疾病的临床试验中测试了 SPM 类似物的有益作用 阐明炎症消退和胆固醇稳态之间的相互作用将为以下方面提供见解 RvD1 类似物作为 NASH 创新治疗策略的潜在用途。