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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：
10735256
负责人：
Michael Karin
金额：
$ 54.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735256
关键词：
Ablation Adult Affect Attenuated Benign Biopsy CASP2 gene Cholesterol Homeostasis Collection Complex Consumption Diet Endoplasmic Reticulum Enzymes Equilibrium Fatty Acids Fatty Liver Fatty acid glycerol esters Feedback Fibrosis Foundations Fructose Genetic Hepatic Hepatocyte High Fat Diet Human Inflammation Inositol Insulin Resistance Link Lipids Liver Mediating Mediator Membrane Metabolic Diseases Modeling Mus Pathogenesis Pathogenicity Pathway interactions Predisposition Regulation Research Role SRE-1 binding protein Scaffolding Protein Signal Transduction Solid Specimen Steatohepatitis Sterols Testing Therapeutic Therapeutic Intervention Time Transducers Wild Type Mouse XBP1 gene burnout endoplasmic reticulum stress inhibitor lipid biosynthesis liver inflammation liver injury mRNA Translation mouse model new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention pharmacologic prevent protein activation sensor simple steatosis site-1 protease therapeutic target transcription factor transcriptomics western diet

项目摘要

Project Summary We have established the existence of an endoplasmic reticulum (ER) stress responsive and caspase 2 (Casp2) dependent pathway that leads to activation of sterol regulatory element binding proteins 1 and 2 (SREBP1/2), the master regulators of fatty acid and cholesterol metabolism. The Casp2-dependent pathway operates independently of SREBP cleavage activation protein (SCAP), the major activator of canonical SREBP signaling and the target for its feedback inhibition and negative regulation by sterols and other lipids. SCAP-dependent SREBP signaling is activated when sterol concentrations are low and during hepatic insulin resistance and may account for simple steatosis (NAFL), the benign form of non-alcoholic fatty liver disease (NAFLD). Conversely, the Casp2-dependent pathway is activated during hepatocyte ER stress and leads to non-alcoholic steatohepatitis (NASH), the aggressive form of NAFLD, characterized by liver damage and inflammation, and at advanced stages by loss of liver fat. Importantly, we discovered that the two pathways are engaged in negative crosstalk, such that SCAP-dependent SREBP activation attenuates ER stress, likely via ER membrane expansion, whereas activation of the Casp2-dependent pathway by the ER stress sensor and transducer IRE1 is associated with induction of INSIG2, an inhibitor of SCAP-dependent SREBP activation. Moreover, inhibition of SCAP-dependent SREBP signaling potentiates ER stress, which enhances IRE1 activation, resulting in elevated expression of INSIG2, Casp2 and PIDD1, a component of the PIDDosome complex, which includes Casp2 and the scaffold protein RAIDD. In addition to Casp2 activation, PIDD1 may target the PIDDosome complex to the ER membrane, thereby enabling cleavage of site 1 protease (S1P) by Casp2, the first step in the non-canonical SREBP activation pathway. We postulate that the mutually exclusive interactions between the two pathways contribute to the sharp transition from simple steatosis to NASH. We will test this hypothesis in three specific aims. 1. Test the hypothesis that elevated IRE1 activity, Casp2 activation and inhibition of SCAP- dependent SREBP activation control human NASH progression, using an extensive collection of NAFLD biopsies available at UCSD and a novel human liver spheroid model of NAFLD/NASH. 2. Test the hypothesis that INSIG2 induction inhibits SCAP-dependent SREBP activation and potentiates the Casp2- dependent pathway by enhancing ER stress and IRE1 activation. These studies will be conducted in mouse models and will deploy state-of-the-art high-content spatial transcriptomics. 3. Determine the role of IRE1 and its downstream effectors in NAFL to NASH progression in mouse models and human spheroids, and the suitability of these mediators to therapeutic targeting. Impact: these studies will shed new light on the mechanistic basis for Casp2-dependent SREBP activation and the role of ER stress, IRE1 and its effectors in NASH pathogenesis, laying the foundation to new therapeutic interventions.

项目概要我们已经确定内质网 (ER) 应激反应和 caspase 2 的存在 (Casp2) 依赖性途径导致甾醇调节元件结合蛋白 1 和 2 的激活 (SREBP1/2)，脂肪酸和胆固醇代谢的主要调节因子。 Casp2依赖性该途径独立于 SREBP 裂解激活蛋白 (SCAP) 运行，SCAP 是典型的 SREBP 信号传导及其反馈抑制和甾醇负调节的目标其他脂质。当甾醇浓度较低时，SCAP 依赖性 SREBP 信号被激活肝脏胰岛素抵抗，可能导致单纯性脂肪变性（NAFL），这是非酒精性脂肪变性的良性形式脂肪肝（NAFLD）。相反，Casp2 依赖性途径在肝细胞 ER 过程中被激活压力并导致非酒精性脂肪性肝炎 (NASH)，这是 NAFLD 的侵袭性形式，其特征是肝脏损伤和炎症，晚期则由于肝脏脂肪减少。重要的是，我们发现两条通路参与负串扰，从而导致 SCAP 依赖性 SREBP 激活减轻 ER 应激，可能是通过 ER 膜扩张，而激活 Casp2 依赖性 ER 应激传感器和传感器 IRE1 的通路与 INSIG2（一种抑制剂）的诱导相关 SCAP 依赖性 SREBP 激活。此外，抑制 SCAP 依赖性 SREBP 信号传导增强 ER 应激，从而增强 IRE1 激活，导致 INSIG2、Casp2 表达升高 PIDD1，PIDDosome 复合体的一个组成部分，包括 Casp2 和支架蛋白 RAID。除了 Casp2 激活之外，PIDD1 还可以将 PIDDosome 复合物靶向 ER 膜，从而能够通过 Casp2 切割位点 1 蛋白酶 (S1P)，这是非规范 SREBP 的第一步激活途径。我们假设两条途径之间相互排斥的相互作用有助于从简单的脂肪变性到 NASH 的急剧转变。我们将分三步检验这个假设具体目标。 1. 检验 IRE1 活性升高、Casp2 激活和 SCAP-抑制的假设依赖 SREBP 激活控制人类 NASH 进展，使用广泛的 NAFLD 集合加州大学圣地亚哥分校提供的活检和 NAFLD/NASH 的新型人类肝球模型。 2. 测试假设 INSIG2 诱导抑制 SCAP 依赖性 SREBP 激活并增强 Casp2- 通过增强 ER 应激和 IRE1 激活来抑制依赖性途径。这些研究将在小鼠模型并将部署最先进的高内涵空间转录组学。 3、确定角色 IRE1 及其下游效应子在小鼠模型和人类 NAFL 至 NASH 进展中的作用球体，以及这些介质对治疗靶向的适用性。影响：这些研究将产生影响关于 Casp2 依赖性 SREBP 激活的机制基础以及 ER 应激 IRE1 的作用的新线索及其在 NASH 发病机制中的效应物，为新的治疗干预措施奠定了基础。