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Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods and results: 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 the 14C‐cholesterol and 3H‐sitostanol absorption assay. Similar to our earlier study on Mmp2−/− mice, we observed that Mmp9−/− mice had elevated plasma secreted phospholipase A2 activity. Pharmacological inhibition of systemic circulating secreted phospholipase A2 activity (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.

Conclusions: Our results show that MMP‐9 modulates cholesterol metabolism, at least in part, through a novel MMP‐9–plasma secreted phospholipase A2 axis 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.

No MeSH data available.


Related in: MedlinePlus

The MMP system modulates hepatic transcriptional responses to dietary cholesterol. A, Deficiency of MMP‐2, MMP‐7, or MMP‐9 is associated with abnormalities in the hepatic transcriptional responses to dietary cholesterol. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 6.5 days. Gene expression analysis was conducted at 0, 2.5, and 6.5 days. Analysis involved 6 WT mice, 8Mmp2−/− mice, 5 Mmp7−/− mice, and 5 Mmp9−/− mice. For clarity, the symbols indicating statistically significant differences were excluded. An expanded version of these analyses is presented in Figure S6. B, Proposed model for regulation of cholesterol homeostasis by systemic MMP activity. MMP deficiencies (due to genetic deletion or functional blockade) can alter the hepatic cholesterol metabolism. The mechanism by which MMPs act may or may not require the release of sPLA2 activity from peripheral organs and is governed by tissue inhibitors of metalloproteinase. Cyp27a1 indicates sterol 27 hydroxylase; Cyp7a1, cholesterol 7 alpha hydroxylase; Fasn, fatty acid synthase; Hmgcr, 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase; Ldlr, low density lipoprotein receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; sPLA2, secreted phospholipase A2; Srebf1, sterol regulatory element binding protein 1; Srebf2, gene for sterol regulatory element binding protein 2; TIMP, tissue inhibitor of metalloproteinase; WT, wild type.
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jah31792-fig-0006: The MMP system modulates hepatic transcriptional responses to dietary cholesterol. A, Deficiency of MMP‐2, MMP‐7, or MMP‐9 is associated with abnormalities in the hepatic transcriptional responses to dietary cholesterol. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 6.5 days. Gene expression analysis was conducted at 0, 2.5, and 6.5 days. Analysis involved 6 WT mice, 8Mmp2−/− mice, 5 Mmp7−/− mice, and 5 Mmp9−/− mice. For clarity, the symbols indicating statistically significant differences were excluded. An expanded version of these analyses is presented in Figure S6. B, Proposed model for regulation of cholesterol homeostasis by systemic MMP activity. MMP deficiencies (due to genetic deletion or functional blockade) can alter the hepatic cholesterol metabolism. The mechanism by which MMPs act may or may not require the release of sPLA2 activity from peripheral organs and is governed by tissue inhibitors of metalloproteinase. Cyp27a1 indicates sterol 27 hydroxylase; Cyp7a1, cholesterol 7 alpha hydroxylase; Fasn, fatty acid synthase; Hmgcr, 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase; Ldlr, low density lipoprotein receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; sPLA2, secreted phospholipase A2; Srebf1, sterol regulatory element binding protein 1; Srebf2, gene for sterol regulatory element binding protein 2; TIMP, tissue inhibitor of metalloproteinase; WT, wild type.

Mentions: Figures 3 and 6A indicate that either increasing dietary cholesterol from moderate (0.15%) to high (1.5%) over 2.5 days or extending cholesterol administration from 2.5 to 6.5 days resulted in the partial normalization of hepatic gene transcriptional responses of Mmp9−/− mice, suggesting a finite contribution of MMP‐9 to regulation of cholesterol metabolism. We next compared the liver function of Mmp9−/− and WT mice fed an HFD for 15 weeks (from 5 to 20 weeks of age) versus mice fed a standard fat diet. At 5 weeks of age, Mmp9−/− and WT mice had similar body weights. The HFD markedly increased the levels of alkaline phosphatases and alanine and aspartate aminotransferases in both WT and Mmp9−/− mice (versus standard fat diet); however, feeding the HFD did not differently influence plasma lipids,12 body weight, liver weight, or plasma levels of alkaline phosphatases or alanine and aspartate aminotransferases of Mmp9−/− versus WT mice (Table).


Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism
The MMP system modulates hepatic transcriptional responses to dietary cholesterol. A, Deficiency of MMP‐2, MMP‐7, or MMP‐9 is associated with abnormalities in the hepatic transcriptional responses to dietary cholesterol. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 6.5 days. Gene expression analysis was conducted at 0, 2.5, and 6.5 days. Analysis involved 6 WT mice, 8Mmp2−/− mice, 5 Mmp7−/− mice, and 5 Mmp9−/− mice. For clarity, the symbols indicating statistically significant differences were excluded. An expanded version of these analyses is presented in Figure S6. B, Proposed model for regulation of cholesterol homeostasis by systemic MMP activity. MMP deficiencies (due to genetic deletion or functional blockade) can alter the hepatic cholesterol metabolism. The mechanism by which MMPs act may or may not require the release of sPLA2 activity from peripheral organs and is governed by tissue inhibitors of metalloproteinase. Cyp27a1 indicates sterol 27 hydroxylase; Cyp7a1, cholesterol 7 alpha hydroxylase; Fasn, fatty acid synthase; Hmgcr, 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase; Ldlr, low density lipoprotein receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; sPLA2, secreted phospholipase A2; Srebf1, sterol regulatory element binding protein 1; Srebf2, gene for sterol regulatory element binding protein 2; TIMP, tissue inhibitor of metalloproteinase; WT, wild type.
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getmorefigures.php?uid=PMC5121519&req=5

jah31792-fig-0006: The MMP system modulates hepatic transcriptional responses to dietary cholesterol. A, Deficiency of MMP‐2, MMP‐7, or MMP‐9 is associated with abnormalities in the hepatic transcriptional responses to dietary cholesterol. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 6.5 days. Gene expression analysis was conducted at 0, 2.5, and 6.5 days. Analysis involved 6 WT mice, 8Mmp2−/− mice, 5 Mmp7−/− mice, and 5 Mmp9−/− mice. For clarity, the symbols indicating statistically significant differences were excluded. An expanded version of these analyses is presented in Figure S6. B, Proposed model for regulation of cholesterol homeostasis by systemic MMP activity. MMP deficiencies (due to genetic deletion or functional blockade) can alter the hepatic cholesterol metabolism. The mechanism by which MMPs act may or may not require the release of sPLA2 activity from peripheral organs and is governed by tissue inhibitors of metalloproteinase. Cyp27a1 indicates sterol 27 hydroxylase; Cyp7a1, cholesterol 7 alpha hydroxylase; Fasn, fatty acid synthase; Hmgcr, 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase; Ldlr, low density lipoprotein receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; sPLA2, secreted phospholipase A2; Srebf1, sterol regulatory element binding protein 1; Srebf2, gene for sterol regulatory element binding protein 2; TIMP, tissue inhibitor of metalloproteinase; WT, wild type.
Mentions: Figures 3 and 6A indicate that either increasing dietary cholesterol from moderate (0.15%) to high (1.5%) over 2.5 days or extending cholesterol administration from 2.5 to 6.5 days resulted in the partial normalization of hepatic gene transcriptional responses of Mmp9−/− mice, suggesting a finite contribution of MMP‐9 to regulation of cholesterol metabolism. We next compared the liver function of Mmp9−/− and WT mice fed an HFD for 15 weeks (from 5 to 20 weeks of age) versus mice fed a standard fat diet. At 5 weeks of age, Mmp9−/− and WT mice had similar body weights. The HFD markedly increased the levels of alkaline phosphatases and alanine and aspartate aminotransferases in both WT and Mmp9−/− mice (versus standard fat diet); however, feeding the HFD did not differently influence plasma lipids,12 body weight, liver weight, or plasma levels of alkaline phosphatases or alanine and aspartate aminotransferases of Mmp9−/− versus WT mice (Table).

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods and results: 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 the 14C‐cholesterol and 3H‐sitostanol absorption assay. Similar to our earlier study on Mmp2−/− mice, we observed that Mmp9−/− mice had elevated plasma secreted phospholipase A2 activity. Pharmacological inhibition of systemic circulating secreted phospholipase A2 activity (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.

Conclusions: Our results show that MMP‐9 modulates cholesterol metabolism, at least in part, through a novel MMP‐9–plasma secreted phospholipase A2 axis 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.

No MeSH data available.


Related in: MedlinePlus