Studies on the mechanism by which MMP-7 modulates cholesterol metabolism

MMP-7调节胆固醇代谢的机制研究

• 批准号: RGPIN-2017-05698
• 负责人: FernandezPatron, Carlos
• 金额: $ 1.89万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711391
• 关键词: Studies; mechanism; MMP; modulates; cholesterol

Background: Cholesterol biosynthesis is inhibited by intracellular cholesterol, which leads to transcriptional down-regulation of cholesterol biosynthetic enzymes through blockade of the activation of SREBP-2, a member of the sterol regulatory element-binding protein family of transcription factors. Matrix metalloproteinases (MMPs) are collectively responsible for tissue remodeling but not typically viewed as major metabolic modulators. This NSERC Discovery Grant will challenge this notion through original studies targeting the smallest member of the MMP family, MMP-7 also known as matrilysin, which we propose modulates hepatic SREBP-dependent responses to cholesterol via a novel physiological pathway. Rationale: In preliminary studies, we discovered that the lack of MMP-7 impairs the transcriptional responses of hepatic SREBP-2 target genes to dietary cholesterol supplementation in mice. Furthermore, we identified a pathogenic release of a pro-inflammatory phospholipase A2 (sPLA2) from organs into circulation resulting in hepatic inflammation in Mmp7-/- mice. Although we have not yet comprehensively investigated the physiology of Mmp7-/- mice, we know that the inhibition of systemic circulating sPLA2 partially normalizes hepatic inflammation and the hepatic transcriptional responses of genes in the SREBP-2 pathway to dietary cholesterol in Mmp2-/- and Mmp9-/- mice. MMP-7 could modulate hepatic cholesterol metabolism through a similar mechanism involving sPLA2. Specific hypothesis: MMP-7 modulates cholesterol metabolism through the negative regulation of a novel sPLA2/hepatic inflammation/SREBP-2 axis. Aim 1 Characterize the sPLA2(s) regulated by MMP-7 at the molecular level. Aim 2 Map the biological pathways by which the MMP-7/sPLA2 axis modulates the SREBP-2 pathway. Overall strategy: We will address our hypothesis in two complementary mouse models: Mmp7-/- mice (with full body MMP-7 deficiency) and Mmp7(flox/flox) x Alb-cre mice (with liver-specific MMP-7 knockdown). The 1st model will allow us to test the hypothesis that peripheral organs influence the metabolism of the liver through sPLA2, which serves as a metabolic signal. The 2nd model will allow us to delineate the specific role of hepatic MMP-7 in modulation of the hepatic SREBP-2 pathway. Two graduate students will drive this research. We will pursue these projects with long-standing collaborators in Canada, France, USA and Japan. Significance: The postulated MMP-7/sPLA2/hepatic inflammation/SREBP-2 axis is a novel biochemical mechanism of systemic modulation of cholesterol homeostasis with potential significance in health and disease.

背景：胆固醇生物合成受到细胞内胆固醇的抑制，通过阻断 SREBP-2（转录因子甾醇调节元件结合蛋白家族的成员）的激活，导致胆固醇生物合成酶的转录下调。 基质金属蛋白酶 (MMP) 共同负责组织重塑，但通常不被视为主要的代谢调节剂。这项 NSERC 发现补助金将通过针对 MMP 家族最小成员 MMP-7（也称为基质溶解素）的原创研究挑战这一概念，我们建议 MMP-7 通过一种新的生理途径调节肝脏对胆固醇的 SREBP 依赖性反应。 理由：在初步研究中，我们发现 MMP-7 的缺乏会损害小鼠肝脏 SREBP-2 靶基因对膳食胆固醇补充剂的转录反应。此外，我们还发现促炎性磷脂酶 A2 (sPLA2) 从器官释放到循环系统中，导致 Mmp7-/- 小鼠出现肝脏炎症。尽管我们还没有全面研究Mmp7-/-小鼠的生理学，但我们知道，抑制全身循环sPLA2可以部分使肝脏炎症和SREBP-2途径中基因对Mmp2-/-中膳食胆固醇的肝脏转录反应正常化。和 Mmp9-/- 小鼠。 MMP-7 可以通过涉及 sPLA2 的类似机制调节肝脏胆固醇代谢。 具体假设：MMP-7 通过新型 sPLA2/肝脏炎症/SREBP-2 轴的负调节来调节胆固醇代谢。 目标 1 在分子水平表征 MMP-7 调节的 sPLA2。 目标 2 绘制 MMP-7/sPLA2 轴调节 SREBP-2 途径的生物途径。 总体策略：我们将在两种互补的小鼠模型中阐述我们的假设：Mmp7-/- 小鼠（全身 MMP-7 缺陷）和 Mmp7(flox/flox) x Alb-cre 小鼠（肝脏特异性 MMP-7 敲低） 。第一个模型将使我们能够检验以下假设：外周器官通过 sPLA2（作为代谢信号）影响肝脏的代谢。第二个模型将使我们能够描绘肝脏 MMP-7 在肝脏 SREBP-2 通路调节中的具体作用。两名研究生将推动这项研究。我们将与加拿大、法国、美国和日本的长期合作者一起开展这些项目。 意义：假设的 MMP-7/sPLA2/肝脏炎症/SREBP-2 轴是胆固醇稳态系统调节的一种新的生化机制，对健康和疾病具有潜在意义。