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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.


Circulating systemic sPLA2 modulates hepatic transcriptional responses to dietary cholesterol supplementation. A, Plasma sPLA2 activity ofMmp9−/− mice administered the pan‐sPLA2 inhibitor varespladib (10 mg/kg per day) or vehicle for 5 days (n=4 mice per group). *P<0.05 vs WT, t test. †P<0.05 vs untreated, t test. B, Study protocol for varespladib treatment prior to cholesterol supplementation. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 2.5 days. Varespladib treatment (10 mg/kg per day for 5 days) started 2.5 days prior to commencement of cholesterol supplementation of the diet. C, Hepatic expression of lipid metabolic genes in WT mice administered varespladib (10 mg/kg per day; n=8 WT without varespladib and n=8 WT with varespladib mice, n=4 per time point). *P≤0.05 vs WT without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. D, Hepatic expression of lipid‐metabolic genes in Mmp9−/− mice administered varespladib (10 mg/kg per day; n=8 Mmp9−/− without varespladib and n=8 Mmp9−/− with varespladib, n=4 per time point). *P<0.05 vs Mmp9−/− without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. Abca1 indicates ATP‐binding cassette sub‐family A member 1; Abcg5/Abcg8, ATP‐binding cassette sub‐family G member 5/8; Cyp27a1, 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3/Nr1h2, liver X receptor α/β; 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; SREBP, sterol regulatory element binding protein; WT, wild type.
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jah31792-fig-0005: Circulating systemic sPLA2 modulates hepatic transcriptional responses to dietary cholesterol supplementation. A, Plasma sPLA2 activity ofMmp9−/− mice administered the pan‐sPLA2 inhibitor varespladib (10 mg/kg per day) or vehicle for 5 days (n=4 mice per group). *P<0.05 vs WT, t test. †P<0.05 vs untreated, t test. B, Study protocol for varespladib treatment prior to cholesterol supplementation. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 2.5 days. Varespladib treatment (10 mg/kg per day for 5 days) started 2.5 days prior to commencement of cholesterol supplementation of the diet. C, Hepatic expression of lipid metabolic genes in WT mice administered varespladib (10 mg/kg per day; n=8 WT without varespladib and n=8 WT with varespladib mice, n=4 per time point). *P≤0.05 vs WT without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. D, Hepatic expression of lipid‐metabolic genes in Mmp9−/− mice administered varespladib (10 mg/kg per day; n=8 Mmp9−/− without varespladib and n=8 Mmp9−/− with varespladib, n=4 per time point). *P<0.05 vs Mmp9−/− without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. Abca1 indicates ATP‐binding cassette sub‐family A member 1; Abcg5/Abcg8, ATP‐binding cassette sub‐family G member 5/8; Cyp27a1, 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3/Nr1h2, liver X receptor α/β; 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; SREBP, sterol regulatory element binding protein; WT, wild type.

Mentions: To determine whether the systemic circulating plasma sPLA2 activity mediated the hepatic transcriptional responses to dietary cholesterol in Mmp9−/− mice, we administered the sPLA2 inhibitor varespladib (or vehicle) to Mmp9−/− mice prior to dietary cholesterol supplementation (Figure 5). Administration of varespladib for 5 consecutive days fully normalized the levels of plasma sPLA2 activity in Mmp9−/− mice (Figure 5A). In WT mice, varespladib did not affect the hepatic transcriptional responses to dietary cholesterol (Figure 5B and 5C). In Mmp9−/− mice, varespladib partially normalized the hepatic transcriptional response to cholesterol for genes in the SREBP‐2 pathway (Figure 5D and Figure S4); however, varespladib failed to affect mRNA levels of the rate‐limiting enzymes in biliary cholesterol synthesis (Cyp7a1 and Cyp27a) (Figure 5D).


Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism
Circulating systemic sPLA2 modulates hepatic transcriptional responses to dietary cholesterol supplementation. A, Plasma sPLA2 activity ofMmp9−/− mice administered the pan‐sPLA2 inhibitor varespladib (10 mg/kg per day) or vehicle for 5 days (n=4 mice per group). *P<0.05 vs WT, t test. †P<0.05 vs untreated, t test. B, Study protocol for varespladib treatment prior to cholesterol supplementation. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 2.5 days. Varespladib treatment (10 mg/kg per day for 5 days) started 2.5 days prior to commencement of cholesterol supplementation of the diet. C, Hepatic expression of lipid metabolic genes in WT mice administered varespladib (10 mg/kg per day; n=8 WT without varespladib and n=8 WT with varespladib mice, n=4 per time point). *P≤0.05 vs WT without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. D, Hepatic expression of lipid‐metabolic genes in Mmp9−/− mice administered varespladib (10 mg/kg per day; n=8 Mmp9−/− without varespladib and n=8 Mmp9−/− with varespladib, n=4 per time point). *P<0.05 vs Mmp9−/− without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. Abca1 indicates ATP‐binding cassette sub‐family A member 1; Abcg5/Abcg8, ATP‐binding cassette sub‐family G member 5/8; Cyp27a1, 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3/Nr1h2, liver X receptor α/β; 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; SREBP, sterol regulatory element binding protein; WT, wild type.
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jah31792-fig-0005: Circulating systemic sPLA2 modulates hepatic transcriptional responses to dietary cholesterol supplementation. A, Plasma sPLA2 activity ofMmp9−/− mice administered the pan‐sPLA2 inhibitor varespladib (10 mg/kg per day) or vehicle for 5 days (n=4 mice per group). *P<0.05 vs WT, t test. †P<0.05 vs untreated, t test. B, Study protocol for varespladib treatment prior to cholesterol supplementation. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 2.5 days. Varespladib treatment (10 mg/kg per day for 5 days) started 2.5 days prior to commencement of cholesterol supplementation of the diet. C, Hepatic expression of lipid metabolic genes in WT mice administered varespladib (10 mg/kg per day; n=8 WT without varespladib and n=8 WT with varespladib mice, n=4 per time point). *P≤0.05 vs WT without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. D, Hepatic expression of lipid‐metabolic genes in Mmp9−/− mice administered varespladib (10 mg/kg per day; n=8 Mmp9−/− without varespladib and n=8 Mmp9−/− with varespladib, n=4 per time point). *P<0.05 vs Mmp9−/− without varespladib at day 2.5. †P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. Abca1 indicates ATP‐binding cassette sub‐family A member 1; Abcg5/Abcg8, ATP‐binding cassette sub‐family G member 5/8; Cyp27a1, 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3/Nr1h2, liver X receptor α/β; 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; SREBP, sterol regulatory element binding protein; WT, wild type.
Mentions: To determine whether the systemic circulating plasma sPLA2 activity mediated the hepatic transcriptional responses to dietary cholesterol in Mmp9−/− mice, we administered the sPLA2 inhibitor varespladib (or vehicle) to Mmp9−/− mice prior to dietary cholesterol supplementation (Figure 5). Administration of varespladib for 5 consecutive days fully normalized the levels of plasma sPLA2 activity in Mmp9−/− mice (Figure 5A). In WT mice, varespladib did not affect the hepatic transcriptional responses to dietary cholesterol (Figure 5B and 5C). In Mmp9−/− mice, varespladib partially normalized the hepatic transcriptional response to cholesterol for genes in the SREBP‐2 pathway (Figure 5D and Figure S4); however, varespladib failed to affect mRNA levels of the rate‐limiting enzymes in biliary cholesterol synthesis (Cyp7a1 and Cyp27a) (Figure 5D).

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&#8208;9&ndash;deficient (Mmp9&minus;/&minus;) mice and found them to have abnormal lipid gene transcriptional responses to dietary cholesterol supplementation. As opposed to Mmp9+/+ (wild&#8208;type) mice, Mmp9&minus;/&minus; 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&minus;/&minus; mice failed to increase the expression of genes encoding the rate&#8208;limiting enzymes in biliary cholesterol excretion (eg, Cyp7a and Cyp27a). In contrast, MMP&#8208;9 deficiency did not impair intestinal cholesterol absorption, as shown by the 14C&#8208;cholesterol and 3H&#8208;sitostanol absorption assay. Similar to our earlier study on Mmp2&minus;/&minus; mice, we observed that Mmp9&minus;/&minus; 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&minus;/&minus; 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&#8208;9 modulates cholesterol metabolism, at least in part, through a novel MMP&#8208;9&ndash;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.