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，这会导致胆固醇生物合成酶的转录下调，通过阻断SREBP-2的激活，SREBP-2的激活，SREBP-2（固醇调节性元素结合蛋白的转录因子的蛋白质家族）的成员。 基质金属蛋白酶（MMP）集体负责组织重塑，但通常不视为主要代谢调节剂。这项NSERC发现赠款将通过针对MMP家族中最小的成员MMP-7的原始研究挑战这一概念，也称为Matrilysin，我们建议通过新的生理途径调节肝脏SREBP依赖于胆固醇的反应。 理由：在初步研究中，我们发现缺乏MMP-7损害了肝SREBP-2靶基因对小鼠饮食胆固醇补充的转录反应。此外，我们确定了从器官到循环的促炎磷脂酶A2（SPLA2）的致病释放，导致MMP7 - / - 小鼠的肝炎。尽管我们尚未全面研究MMP7 - / - 小鼠的生理学，但我们知道，抑制系统循环SPLA2的抑制作用使肝炎炎症和MMP2 - / - / - - / - 和MMP9 - / - / - / - / - / - / - / - / - / - / - / - / - 小鼠的肝炎症状和基因基因的肝转录反应归一化。 MMP-7可以通过涉及SPLA2的类似机制来调节肝胆固醇代谢。 具体假设：MMP-7通过新型SPLA2/肝发炎/SREBP-2轴的负调节调节胆固醇代谢。 AIM 1表征了由MMP-7在分子水平上调节的SPLA2。 AIM 2绘制MMP-7/SPLA2轴调节SREBP-2途径的生物学途径。 总体策略：我们将在两种互补的小鼠模型中解决我们的假设：MMP7 - / - 小鼠（具有全身MMP-7缺陷）和MMP7（Flox/Flox）X Alb-Cre小鼠（具有肝脏特异性MMP-7敲低）。第一个模型将使我们能够测试外围器官通过SPLA2影响肝脏的代谢的假设，后者用作代谢信号。第二个模型将使我们能够描述肝MMP-7在肝SREBP-2途径调制中的特定作用。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从事这些项目。 意义：假定的MMP-7/SPLA2/肝发炎/SREBP-2轴是一种新型的胆固醇稳态调节的生化机制，对健康和疾病具有潜在的意义。