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

基本信息

  • 批准号:
    10568478
  • 负责人:
  • 金额:
    $ 56.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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/文摘

项目成果

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Bishuang Cai其他文献

Bishuang Cai的其他文献

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{{ truncateString('Bishuang Cai', 18)}}的其他基金

EHD1-mediated Inflammation and Resolution in Atherosclerosis
EHD1 介导的动脉粥样硬化炎症和消退
  • 批准号:
    10568133
  • 财政年份:
    2023
  • 资助金额:
    $ 56.08万
  • 项目类别:
Efferocytosis meets endocytosis
胞吞作用遇上内吞作用
  • 批准号:
    10795494
  • 财政年份:
    2022
  • 资助金额:
    $ 56.08万
  • 项目类别:
Efferocytosis meets endocytosis
胞吞作用遇上内吞作用
  • 批准号:
    10673780
  • 财政年份:
    2022
  • 资助金额:
    $ 56.08万
  • 项目类别:
MerTK in NASH-related liver fibrosis
MerTK 在 NASH 相关肝纤维化中的作用
  • 批准号:
    10201897
  • 财政年份:
    2020
  • 资助金额:
    $ 56.08万
  • 项目类别:
MerTK in NASH-related liver fibrosis
MerTK 在 NASH 相关肝纤维化中的作用
  • 批准号:
    10216245
  • 财政年份:
    2020
  • 资助金额:
    $ 56.08万
  • 项目类别:
MerTK in NASH-related liver fibrosis
MerTK 在 NASH 相关肝纤维化中的作用
  • 批准号:
    10397618
  • 财政年份:
    2020
  • 资助金额:
    $ 56.08万
  • 项目类别:
MerTK in NASH-related liver fibrosis
MerTK 在 NASH 相关肝纤维化中的作用
  • 批准号:
    9598428
  • 财政年份:
    2018
  • 资助金额:
    $ 56.08万
  • 项目类别:

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促进NAD合成代谢以延长寿命
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    Discovery Early Career Researcher Award
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