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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.


Hepatic transcriptional responses to dietary cholesterol supplementation. Mice were fed regular chow or chow supplemented with cholesterol (0.15%) for up to 2.5 days. Gene expression analysis was conducted at days 0 and 2.5 (n=4 to 5 mice per time point). *P<0.05 vs WT. †P<0.05 vs 0 days on cholesterol, 1‐way repeated‐measures 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; Mmp, matrix metalloproteinase gene; Nr1h3/Nr1h2, liver X receptor α/β; 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-0002: Hepatic transcriptional responses to dietary cholesterol supplementation. Mice were fed regular chow or chow supplemented with cholesterol (0.15%) for up to 2.5 days. Gene expression analysis was conducted at days 0 and 2.5 (n=4 to 5 mice per time point). *P<0.05 vs WT. †P<0.05 vs 0 days on cholesterol, 1‐way repeated‐measures 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; Mmp, matrix metalloproteinase gene; Nr1h3/Nr1h2, liver X receptor α/β; 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: Quantitative reverse transcriptase polymerase chain reaction analysis indicated no difference between Mmp9−/− and WT mice in the expression of Nr1h3 (encoding liver X receptor α [LXR‐α], a major regulator of fatty acid synthesis and cholesterol excretion). Fasn (encodes fatty acid synthase) is an LXR‐α target and was also unaltered. Similarly unchanged were Srebf2 (encodes the transcription factor SREBP‐2) and SREBP‐2 target genes such as Hmgcr (encodes 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, the rate‐limiting enzyme in the cholesterol and isoprenoid synthesis pathways) and Ldlr (encodes the LDL receptor, which is involved in clearance of low‐density lipoprotein from circulation). Paradoxically,2 LXR‐α target genes, the cholesterol transporters ATP‐binding cassette G5 and G8 (encoded by Abcg5 and Abcg8) and the SREBP‐2 target gene Pcsk9 (encodes proprotein convertase subtilisin/kexin type 9, a protein that binds and negatively regulates hepatic LDLR protein levels33) were all significantly higher at baseline in Mmp9−/− mice than in WT mice (Figure 2).


Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism
Hepatic transcriptional responses to dietary cholesterol supplementation. Mice were fed regular chow or chow supplemented with cholesterol (0.15%) for up to 2.5 days. Gene expression analysis was conducted at days 0 and 2.5 (n=4 to 5 mice per time point). *P<0.05 vs WT. †P<0.05 vs 0 days on cholesterol, 1‐way repeated‐measures 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; Mmp, matrix metalloproteinase gene; Nr1h3/Nr1h2, liver X receptor α/β; 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-0002: Hepatic transcriptional responses to dietary cholesterol supplementation. Mice were fed regular chow or chow supplemented with cholesterol (0.15%) for up to 2.5 days. Gene expression analysis was conducted at days 0 and 2.5 (n=4 to 5 mice per time point). *P<0.05 vs WT. †P<0.05 vs 0 days on cholesterol, 1‐way repeated‐measures 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; Mmp, matrix metalloproteinase gene; Nr1h3/Nr1h2, liver X receptor α/β; 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: Quantitative reverse transcriptase polymerase chain reaction analysis indicated no difference between Mmp9−/− and WT mice in the expression of Nr1h3 (encoding liver X receptor α [LXR‐α], a major regulator of fatty acid synthesis and cholesterol excretion). Fasn (encodes fatty acid synthase) is an LXR‐α target and was also unaltered. Similarly unchanged were Srebf2 (encodes the transcription factor SREBP‐2) and SREBP‐2 target genes such as Hmgcr (encodes 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, the rate‐limiting enzyme in the cholesterol and isoprenoid synthesis pathways) and Ldlr (encodes the LDL receptor, which is involved in clearance of low‐density lipoprotein from circulation). Paradoxically,2 LXR‐α target genes, the cholesterol transporters ATP‐binding cassette G5 and G8 (encoded by Abcg5 and Abcg8) and the SREBP‐2 target gene Pcsk9 (encodes proprotein convertase subtilisin/kexin type 9, a protein that binds and negatively regulates hepatic LDLR protein levels33) were all significantly higher at baseline in Mmp9−/− mice than in WT mice (Figure 2).

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.