Function and Mechanism of DDB1-CUL4A E3 Ligase in Liver Lipid Metabolism

DDB1-CUL4A E3连接酶在肝脏脂质代谢中的功能和机制

基本信息

  • 批准号:
    8820262
  • 负责人:
  • 金额:
    $ 33.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-04-01 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Non-alcoholic liver steatosis, also called fatty liver, is due to excessive fat accumulation in hepatocytes and is the most common liver disease affecting 10-30% of the general population. Fatty liver is also regarded as a component of metabolic syndrome, and is associated with insulin resistance, obesity, and diabetes. Nearly 35% of patients with fatty liver develop chronic inflammation, fibrosis, and eventual liver failure and there is no effective treatment for fatty liver disease. Therefore, it is imperative to understand the molecular mechanisms underlying the development of fatty liver. Our preliminary studies demonstrate that the damage-specific DNA binding protein 1 (DDB1) E3 ligase plays a crucial role in the development of high-fat diet (HFD)-induced fatty liver. In particular, we discovered that liver DDB1 protein levels were elevated under obese conditions. Liver-specific deletion of Ddb1 protects mice from the HFD-induced fat accumulation and selectively suppresses glycolytic and lipogenic gene expression in the liver. In primary mouse hepatocytes, Ddb1 knockdown represses de novo lipogenesis rate, reduces triglyceride content, and blocks the activity of a key regulator of lipogenesis, carbohydrate responsive- element binding protein (ChREBP). At the mechanistic level, we uncovered evidence that DDB1 indirectly regulates the ChREBP protein O-GlcNAcylation and stability by degrading O-GlcNAcase (OGA) through ubiquitination. Although DDB1 has been well-studied in the context of DNA damage response as a critical component of the CUL4A E3 ligase complex, its metabolic actions remain unknown. Based upon the preliminary data, we hypothesize that DDB1 E3 ligase contributes to the development of fatty liver by activating ChREBP-mediated hepatic lipogenesis. To test this hypothesis, we propose three inter- connected specific aims. Aim 1: Determine whether the DDB1 E3 ligase promotes de novo lipogenesis and contributes to obesity-associated fatty liver via ChREBP. Aim 2: Test whether DDB1 E3 ligase promotes O- GlcNAcylation and stability of ChREBP via degrading OGA protein in obesity. Aim 3: Investigate how the AMPK pathway mediates nutritional regulation of hepatic DDB1 expression during the obesity development. This proposal seeks an in-depth understanding of the metabolic role of DDB1 E3 ligase. Specifically, we anticipate identifying how DDB1 E3 ligase regulates de novo lipogenesis in the liver and induces fatty liver through ChREBP. Accomplishment of these research objectives should reveal fundamental mechanisms by which nutrient excess leads to fat accumulation and provide potential novel therapeutic avenues to treat fatty liver disease.
描述(申请人提供):非酒精性肝脏脂肪变性,也称为脂肪肝,是由于脂肪在肝细胞中过度堆积而引起的,是最常见的肝脏疾病,影响普通人群的10%-30%。脂肪肝也被认为是代谢综合征的一个组成部分,并与胰岛素抵抗、肥胖和糖尿病有关。近35%的脂肪肝患者发展为慢性炎症、纤维化和最终的肝功能衰竭,目前还没有有效的治疗脂肪肝的方法。因此,了解脂肪肝发生的分子机制势在必行。我们的初步研究表明,损伤特异性DNA结合蛋白1(DDB1)E3连接酶在高脂饮食(HFD)诱导的脂肪肝的发生发展中起着至关重要的作用。特别是,我们发现在肥胖条件下,肝脏DDB1蛋白水平升高。肝脏特异的DDB1缺失可以保护小鼠免受高脂饲料诱导的脂肪堆积,并选择性地抑制肝脏中糖酵解和造脂基因的表达。在原代小鼠肝细胞中,DDB1基因敲除抑制新生脂肪生成速率,降低甘油三酯含量,并阻断脂肪生成的关键调节因子-碳水化合物反应元件结合蛋白(ChREBP)的活性。在机制水平上,我们发现了DDB1通过泛素化降解O-GlcNAcase(OGA)来间接调节ChREBP蛋白O-GlcN酰化和稳定性的证据。虽然DDB1作为CUL4A E3连接酶复合体的重要组成部分已经在DNA损伤反应中得到了很好的研究,但它的代谢作用仍然不清楚。根据初步数据,我们推测DDB1E3连接酶通过激活ChREBP介导的肝脏脂肪生成而参与脂肪肝的发展。为了检验这一假设,我们提出了三个相互关联的具体目标。目的1:确定DDB1E3连接酶是否通过ChREBP促进新生脂肪生成并参与肥胖相关性脂肪肝的发生。目的2:检测DDB1 E3连接酶是否通过降解肥胖大鼠的OGA蛋白来促进O-GlcN酰化和ChREBP的稳定性。目的:探讨AMPK通路在肥胖形成过程中对肝脏DDB1表达的营养调节作用。这项建议寻求深入了解DDB1E3连接酶的代谢作用。具体地说,我们期望确定DDB1 E3连接酶如何通过ChREBP调节肝脏中的新生脂肪生成和诱导脂肪肝。这些研究目标的完成将揭示营养过剩导致脂肪堆积的基本机制,并为治疗脂肪肝提供潜在的新的治疗途径。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Lei Yin其他文献

Ultrarobust support vector registration
超鲁棒支持向量配准
  • DOI:
    10.1007/s10489-020-01967-y
  • 发表时间:
    2020-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Lei Yin;Chong Yu;Yuyi Wang;邹斌;Yuan yan Tang
  • 通讯作者:
    Yuan yan Tang

Lei Yin的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Lei Yin', 18)}}的其他基金

Establishment of human mini-Testis for reproductive toxicity testing
用于生殖毒性测试的人体迷你睾丸的建立
  • 批准号:
    10010729
  • 财政年份:
    2020
  • 资助金额:
    $ 33.74万
  • 项目类别:
Three-dimensional testicular cell co-culture model for reproductive toxicity screening
用于生殖毒性筛查的三维睾丸细胞共培养模型
  • 批准号:
    9789886
  • 财政年份:
    2016
  • 资助金额:
    $ 33.74万
  • 项目类别:
Innovative three-dimensional testicular Co-culture (Mini-Testis) model for reproductive toxicity testing: a pathway based High throughput (HT) and High Content Analysis (HCA)
用于生殖毒性测试的创新三维睾丸共培养(迷你睾丸)模型:基于途径的高通量(HT)和高内涵分析(HCA)
  • 批准号:
    9198371
  • 财政年份:
    2016
  • 资助金额:
    $ 33.74万
  • 项目类别:
BMAL1: A Novel Regulator For Inflammatory Liver Injury
BMAL1:炎症性肝损伤的新型调节剂
  • 批准号:
    8771901
  • 财政年份:
    2015
  • 资助金额:
    $ 33.74万
  • 项目类别:
Significance and mechanisms of hepatic ChREBPα induction via post-translational modifications in diet-induced NASH
通过饮食诱导的 NASH 翻译后修饰诱导肝脏 ChREBPα 的意义和机制
  • 批准号:
    10367324
  • 财政年份:
    2014
  • 资助金额:
    $ 33.74万
  • 项目类别:
Function and Mechanism of DDB1-CUL4A E3 Ligase in Liver Lipid Metabolism
DDB1-CUL4A E3连接酶在肝脏脂质代谢中的功能和机制
  • 批准号:
    9232146
  • 财政年份:
    2014
  • 资助金额:
    $ 33.74万
  • 项目类别:
Function and Mechanism of DDB1-CUL4A E3 Ligase in Liver Lipid Metabolism
DDB1-CUL4A E3连接酶在肝脏脂质代谢中的功能和机制
  • 批准号:
    8697500
  • 财政年份:
    2014
  • 资助金额:
    $ 33.74万
  • 项目类别:
Significance and mechanisms of hepatic ChREBPα induction via post-translational modifications in diet-induced NASH
通过饮食诱导的 NASH 翻译后修饰诱导肝脏 ChREBPα 的意义和机制
  • 批准号:
    10641915
  • 财政年份:
    2014
  • 资助金额:
    $ 33.74万
  • 项目类别:
Biology of nuclear receptor Rev-erb alpha in circadian rhythm and metabolism
核受体 Rev-erb α 在昼夜节律和代谢中的生物学
  • 批准号:
    8136072
  • 财政年份:
    2009
  • 资助金额:
    $ 33.74万
  • 项目类别:
Biology of nuclear receptor Rev-erb alpha in circadian rhythm and metabolism
核受体 Rev-erb α 在昼夜节律和代谢中的生物学
  • 批准号:
    7936289
  • 财政年份:
    2009
  • 资助金额:
    $ 33.74万
  • 项目类别:

相似海外基金

Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
  • 批准号:
    2867610
  • 财政年份:
    2023
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
  • 批准号:
    BB/W009633/1
  • 财政年份:
    2022
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2021
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
  • 批准号:
    459043
  • 财政年份:
    2021
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2020
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10561642
  • 财政年份:
    2019
  • 资助金额:
    $ 33.74万
  • 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2019
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
  • 批准号:
    2243045
  • 财政年份:
    2019
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10359032
  • 财政年份:
    2019
  • 资助金额:
    $ 33.74万
  • 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
  • 批准号:
    428988
  • 财政年份:
    2019
  • 资助金额:
    $ 33.74万
  • 项目类别:
    Studentship Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了