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

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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.