Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism.
The development of atherosclerosis is strongly linked to disorders of cholesterol metabolism. Matrix metalloproteinases (MMPs) are dysregulated in patients and animal models with atherosclerosis. Whether systemic MMP activity influences cholesterol metabolism is unknown.



We examined MMP-9-deficient (Mmp9-/-) mice and found them to have abnormal lipid gene transcriptional responses to dietary cholesterol supplementation. As opposed to Mmp9+/+(wild-type) mice, Mmp9-/-mice failed to decrease the hepatic expression of sterol regulatory element binding protein 2 pathway genes, which control hepatic cholesterol biosynthesis and uptake. Furthermore, Mmp9-/-mice failed to increase the expression of genes encoding the rate-limiting enzymes in biliary cholesterol excretion (eg, Cyp7a and Cyp27a). In contrast, MMP-9 deficiency did not impair intestinal cholesterol absorption, as shown by the14C-cholesterol and3H-sitostanol absorption assay. Similar to our earlier study on Mmp2-/-mice, we observed that Mmp9-/-mice had elevated plasma secreted phospholipase A2activity. Pharmacological inhibition of systemic circulating secreted phospholipase A2activity (with varespladib) partially normalized the hepatic transcriptional responses to dietary cholesterol in Mmp9-/-mice. Functional studies with mice deficient in other MMPs suggested an important role for the MMP system, as a whole, in modulation of cholesterol metabolism.



Our results show that MMP-9 modulates cholesterol metabolism, at least in part, through a novel MMP-9-plasma secreted phospholipase A2axis that affects the hepatic transcriptional responses to dietary cholesterol. Furthermore, the data suggest that dysregulation of the MMP system can result in metabolic disorder, which could lead to atherosclerosis and coronary heart disease.
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Samuel
S
Hernandez-Anzaldo
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, Nice, France.
Vesna
V
Brglez
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
Bianca
B
Hemmeryckx
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Dickson
D
Leung
The Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Canada.
Janos G
JG
Filep
Department of Medicine, Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Jean E
JE
Vance
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Dennis E
DE
Vance
Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Zamaneh
Z
Kassiri
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium cf2@ualberta.ca roger.lijnen@med.kuleuven.be.
Roger H
RH
Lijnen
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, Nice, France.
Gérard
G
Lambeau
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada cf2@ualberta.ca roger.lijnen@med.kuleuven.be.
Carlos
C
Fernandez-Patron
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology; D007408:Intestinal Absorption / Q000235:genetics*; D007651:Keto Acids; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology; D054467:Phospholipases A2 / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000085:Acetates; D007211:Indoles; D007651:Keto Acids; D064801:Phospholipase A2 Inhibitors; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C117948:varespladib; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D054467:Phospholipases A2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
atherosclerosis; cholesterol; lipid metabolism; liver; matrix metalloproteinase; plasma phospholipase A2
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