Control of Lipogenesis and Hepatic Steatosis by Caspase-2

Caspase-2 对脂肪生成和肝脂肪变性的控制

基本信息

  • 批准号:
    10322660
  • 负责人:
  • 金额:
    $ 41.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-03-15 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder whose US incidence exceeds 30%. While NAFLD manifests as benign steatosis, in about 15-20% of patients it assumes a much more aggressive form – non-alcoholic steatohepatitis (NASH). The switch from benign simple steatosis to NASH is poorly understood, but was suggested to depend on ER stress. Indeed, by feeding MUP-uPA mice, which are prone to liver ER stress caused by hepatocyte-specific urokinase plasminogen activator (uPA) expression, a high-fat diet (HFD) we established a faithful model of NASH that readily progresses to hepatocellular carcinoma (HCC). HFD-fed MUP-uPA mice show ER-stress-dependent and persistent activation of sterol response element binding proteins (SREBP) 1 and 2, which control de novo lipogenesis (DNL) and cholesterol biosynthesis. Notably, SREBP1 and 2 remain activated in the MUP-uPA liver without any sign of feedback inhibition, which shuts down their activity in lipid-loaded cells. DNL is also chronically elevated in NAFLD and hepatic accumulation of free cholesterol was suggested to convert simple steatosis to NASH. Investigating how liver ER stress causes persistent SREBP activation, we uncovered a previously unknown pathway in which caspase-2 (Casp2), whose expression is ER-stress-inducible, leads to constitutive activation of site 1 protease (S1P), thereby initiating SCAP-independent SREBP cleavage in the ER. Casp2-mediated cleavage and activation of S1P seems to occur in NASH patients and genetic ablation or pharmacological inhibition of Casp2 in MUP-uPA mice blocks hepatic steatosis and NASH development. To fully establish the mechanistic aspects of this pathway and its role in hepatic steatosis, we will investigate whether it functions in liver-specific SCAP knockout mice and determine whether liver-specific Casp2 ablation affects peripheral adiposity and improves energy expenditure in addition to preventing HFD-induced hepatic steatosis and its progression to NASH. We will also generate knockin mice that express a Casp2-resistant (C2R) form of S1P and determine whether they are protected from ER- stress induced hepatic steatosis and adipose tissue expansion. As ER-stress-mediated Casp2 activation and S1P cleavage seem to depend on Tp53 activity, which results in induction of the Casp2 activator PIDD, we will examine the role of Tp53 and PIDD in Casp2-dependent S1P cleavage, SREBP1/2 activation, and hepatic steatosis, thereby establishing a key metabolic function for Tp53 outside of cancer. Finally, we will examine the hypothesis that the original function of the Casp2-dependent S1P-SREBP activation pathway was to promote energy storage in the form of liver fat during periods of hypernutrition in preparation for long-term starvation. While clarifying the role of Casp2-mediated SREBP activation in hepatic steatosis and NASH, these studies will shed new light on the poorly understood phenomenon of selective insulin resistance, in which hepatic DNL remains elevated despite diminished insulin signaling.
项目摘要 非酒精性脂肪性肝病(NAFLD)是一种常见的代谢紊乱, 百分之三十虽然NAFLD表现为良性脂肪变性,但在约15-20%的患者中, 侵袭性形式-非酒精性脂肪性肝炎(NASH)。从良性单纯性脂肪变性到NASH的转变是 了解不多,但建议依赖于ER应激。事实上,通过喂养MUP-uPA小鼠, 肝细胞特异性尿激酶型纤溶酶原激活物(uPA)的表达容易引起肝内质网应激, 高脂饮食(HFD),我们建立了一个可靠的NASH模型,该模型易于发展为肝细胞癌 (HCC)。HFD喂养的MUP-uPA小鼠显示ER应激依赖性和持续激活的固醇反应元件 结合蛋白(SREBP)1和2,其控制从头脂肪生成(DNL)和胆固醇生物合成。 值得注意的是,SREBP 1和2在MUP-uPA肝脏中保持激活,没有任何反馈抑制的迹象, 关闭了它们在脂质细胞中的活动。DNL在NAFLD和肝硬化中也长期升高。 游离胆固醇的积累被认为将单纯性脂肪变性转化为NASH。研究肝脏ER如何 应激导致持续的SREBP激活,我们发现了一个以前未知的途径,其中caspase-2 (Casp 2),其表达是ER应激诱导的,导致位点1蛋白酶(S1 P)的组成型激活, 从而在ER中启动SCAP非依赖性SREBP切割。Casp 2介导的切割和激活 S1 P似乎发生在NASH患者中,MUP-uPA中Casp 2的遗传消融或药物抑制 小鼠阻断肝脂肪变性和NASH发展。为了完全建立这条途径的机制方面, 及其在肝脂肪变性中的作用,我们将研究它是否在肝脏特异性SCAP敲除小鼠中起作用, 确定肝脏特异性Casp 2消融是否影响外周肥胖并改善能量消耗, 除了预防HFD诱导的肝脂肪变性及其进展为NASH之外。我们还将生成敲入 表达Casp 2-抗性(C2 R)形式的S1 P的小鼠,并确定它们是否被保护免受ER- 应激诱导肝脂肪变性和脂肪组织扩张。由于ER应激介导的Casp 2活化和 S1 P切割似乎依赖于Tp 53活性,其导致Casp 2激活剂PIDD的诱导,我们将 检查Tp 53和PIDD在Casp 2依赖性S1 P切割、SREBP 1/2激活和肝细胞凋亡中的作用。 脂肪变性,从而在癌症之外建立Tp 53的关键代谢功能。最后,我们将研究 假设Casp 2依赖性S1 P-SREBP激活途径的原始功能是促进 在营养过剩时期以肝脏脂肪的形式储存能量,为长期饥饿做准备。 在阐明Casp 2介导的SREBP激活在肝脂肪变性和NASH中的作用的同时,这些研究将 揭示了对选择性胰岛素抵抗知之甚少的现象,其中肝DNL 尽管胰岛素信号减少,但仍然升高。

项目成果

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Michael Karin其他文献

Michael Karin的其他文献

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{{ truncateString('Michael Karin', 18)}}的其他基金

NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
  • 批准号:
    10516935
  • 财政年份:
    2023
  • 资助金额:
    $ 41.77万
  • 项目类别:
A new mouse model for studying the pathogenesis and immunobiology of intrahepatic cholangiocarcinoma and improving its immunotherapy
研究肝内胆管癌发病机制和免疫生物学并改进其免疫治疗的新小鼠模型
  • 批准号:
    10711615
  • 财政年份:
    2023
  • 资助金额:
    $ 41.77万
  • 项目类别:
Regulation of PDAC metabolism and immunity by collagen and its cleavage products
胶原及其裂解产物对 PDAC 代谢和免疫的调节
  • 批准号:
    10708168
  • 财政年份:
    2022
  • 资助金额:
    $ 41.77万
  • 项目类别:
Regulation of PDAC metabolism and immunity by collagen and its cleavage products
胶原及其裂解产物对 PDAC 代谢和免疫的调节
  • 批准号:
    10517874
  • 财政年份:
    2022
  • 资助金额:
    $ 41.77万
  • 项目类别:
The NRF2-FBP1 crossregulatory loop and the control of healthy and diseased liver metabolism
NRF2-FBP1 交叉调节环路以及健康和患病肝脏代谢的控制
  • 批准号:
    10503841
  • 财政年份:
    2022
  • 资助金额:
    $ 41.77万
  • 项目类别:
The NRF2-FBP1 crossregulatory loop and the control of healthy and diseased liver metabolism
NRF2-FBP1 交叉调节环路以及健康和患病肝脏代谢的控制
  • 批准号:
    10670920
  • 财政年份:
    2022
  • 资助金额:
    $ 41.77万
  • 项目类别:
The effect of cancer cell produced collagen 1 homotrimers on DDR1 signaling activation by microenvironmental collagen 1 fragments.
癌细胞产生的胶原蛋白 1 同源三聚体对微环境胶原蛋白 1 片段激活 DDR1 信号传导的影响。
  • 批准号:
    10831212
  • 财政年份:
    2022
  • 资助金额:
    $ 41.77万
  • 项目类别:
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
  • 批准号:
    10182897
  • 财政年份:
    2020
  • 资助金额:
    $ 41.77万
  • 项目类别:
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
  • 批准号:
    10266224
  • 财政年份:
    2020
  • 资助金额:
    $ 41.77万
  • 项目类别:
Control of Lipogenesis and Hepatic Steatosis by Caspase-2
Caspase-2 对脂肪生成和肝脂肪变性的控制
  • 批准号:
    10735256
  • 财政年份:
    2019
  • 资助金额:
    $ 41.77万
  • 项目类别:

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