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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.


Impact of dietary cholesterol on hepatic transcriptional responses. Mice were fed either regular chow or chow supplemented with cholesterol (0.15% or 1.5%) for 2.5 days. Gene expression analysis was conducted at 0 and 2.5 days (n=4 to 5 mice per group [or treatment]). *P<0.05 vs normal chow for each genotype, all pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; Nr1h3/LXR‐α, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; 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-0003: Impact of dietary cholesterol on hepatic transcriptional responses. Mice were fed either regular chow or chow supplemented with cholesterol (0.15% or 1.5%) for 2.5 days. Gene expression analysis was conducted at 0 and 2.5 days (n=4 to 5 mice per group [or treatment]). *P<0.05 vs normal chow for each genotype, all pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; Nr1h3/LXR‐α, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; 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: As expected, WT mice fed chow supplemented with cholesterol exhibited time‐dependent (Figure 2) and concentration‐dependent (Figure 3) decreases in the expression of key genes involved in cholesterol synthesis and uptake: Srebf2, Hmgcr, Ldlr, and Pcsk9. The expression of Fatty acid synthase, a key enzyme in fatty acid biosynthesis, was concentration‐dependently downregulated by cholesterol. In addition, dietary cholesterol unexpectedly increased Abcg5 and Abcg8, caused a small decrease in Nr1h3 and Nh1h2 and strongly induced the expression of Cyp7a1 and Cyp27a, which encode the rate‐limiting enzymes in the classical (cholesterol 7α‐hydroxylase) and alternate (cholesterol 27α‐hydroxylase) bile acid biosynthesis pathways.


Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism
Impact of dietary cholesterol on hepatic transcriptional responses. Mice were fed either regular chow or chow supplemented with cholesterol (0.15% or 1.5%) for 2.5 days. Gene expression analysis was conducted at 0 and 2.5 days (n=4 to 5 mice per group [or treatment]). *P<0.05 vs normal chow for each genotype, all pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; Nr1h3/LXR‐α, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; 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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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5121519&req=5

jah31792-fig-0003: Impact of dietary cholesterol on hepatic transcriptional responses. Mice were fed either regular chow or chow supplemented with cholesterol (0.15% or 1.5%) for 2.5 days. Gene expression analysis was conducted at 0 and 2.5 days (n=4 to 5 mice per group [or treatment]). *P<0.05 vs normal chow for each genotype, all pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. 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; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; Nr1h3/LXR‐α, liver X receptor α; Pcsk9, proprotein convertase subtilisin/kexin type 9; 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: As expected, WT mice fed chow supplemented with cholesterol exhibited time‐dependent (Figure 2) and concentration‐dependent (Figure 3) decreases in the expression of key genes involved in cholesterol synthesis and uptake: Srebf2, Hmgcr, Ldlr, and Pcsk9. The expression of Fatty acid synthase, a key enzyme in fatty acid biosynthesis, was concentration‐dependently downregulated by cholesterol. In addition, dietary cholesterol unexpectedly increased Abcg5 and Abcg8, caused a small decrease in Nr1h3 and Nh1h2 and strongly induced the expression of Cyp7a1 and Cyp27a, which encode the rate‐limiting enzymes in the classical (cholesterol 7α‐hydroxylase) and alternate (cholesterol 27α‐hydroxylase) bile acid biosynthesis pathways.

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.