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:
    9886239
  • 负责人:
  • 金额:
    $ 41.64万
  • 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 2022-12-31
  • 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 非酒精性脂肪肝病(NAFLD)是一种常见的代谢疾病,其美国事件超过 30%。虽然NAFLD表现为良性脂肪变性,但在大约15-20%的患者中,它假设更多 侵略性形式 - 非酒精性脂肪性肝炎(NASH)。从良性简单的脂肪变为纳什的转换是 理解不佳,但建议取决于ER压力。实际上,通过喂食混乱的小鼠 容易发生肝细胞特异性尿激酶纤溶酶原激活剂(UPA)表达,A,A 高脂饮食(HFD),我们建立了一个忠实的NASH模型,该模型很容易发展为肝细胞癌 (HCC)。 HFD喂养的MUP-UPA小鼠显示立体声响应元件的ER应力依赖性和持续激活 结合蛋白(SREBP)1和2,控制从头脂肪生成(DNL)和胆固醇生物合成。 值得注意的是,SREBP1和2仍在混乱的肝脏中激活,而没有任何反馈抑制迹象, 关闭其在脂质负载的细胞中的活性。 DNL在NAFLD和肝脏中也长期升高 建议游离胆固醇的积累将简单的脂肪变性转化为纳什。调查肝脏如何 压力导致持续的SREBP激活,我们发现了一个以前未知的途径,其中caspase-2 (CASP2)的表达是可诱导的,可导致位点1蛋白酶(S1P)的本构激活 从而在ER中引发了与SCAP无关的SREBP裂解。 CASP2介导的裂解和激活 S1P似乎发生在NASH患者,遗传消融或药物抑制CASP2中 小鼠阻止肝脂肪变性和纳什发育。充分建立该途径的机械方面 及其在肝脂肪变性中的作用,我们将研究它在肝特异性的SCAP敲除小鼠和 确定肝特异性CASP2消融是否影响外围肥胖并改善能量消耗 除了防止HFD诱导的肝脂肪变性及其发展为NASH。我们还将产生敲击 表达S1P的CASP2(C2R)形式的小鼠,并确定它们是否受到ER-的保护 压力诱导肝脂肪变性和脂肪组织扩张。作为ER应力介导的CASP2激活和 S1P裂解似乎取决于TP53活性,这导致CASP2激活剂PIDD,我们将 检查TP53和PIDD在CASP2依赖性S1P裂解,SREBP1/2激活和肝的作用 脂肪变性,从而在癌症之外建立了TP53的关键代谢功能。最后,我们将研究 假设CASP2依赖性S1P-SREBP激活途径的原始功能是促进 在生育营养期间,以肝脏脂肪形式储存以准备长期饥饿。 在阐明CASP2介导的SREBP激活在肝脂肪变性和NASH中的作用时,这些研究将 对选择性胰岛素抵抗的现象不理解的现象开发了新的灯光,其中肝DNL 胰岛素信号传导仍保持升高的目的地减少。

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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    $ 41.64万
  • 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:
    10322660
  • 财政年份:
    2019
  • 资助金额:
    $ 41.64万
  • 项目类别:

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