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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

MMP‐9 deficiency is associated with abnormalities in lipid distribution and excretion. A, Triglyceride and cholesterol levels in lipoprotein fractions of plasma separated by FPLC. Traces correspond to pools of plasma from WT and Mmp9−/− mice (n=4 per genotype). Semiquantitative assessment based on peak heights indicates that Mmp9−/− mice have 2.7‐, 4.3‐, 1.5‐, and 1.2‐fold increases in VLDL triglycerides, VLDL cholesterol, LDL cholesterol, and HDL cholesterol, respectively (compared with WT mice). The same volume was injected onto the FPLC. B, Cholesterol absorption measured by radioactive 14C‐cholesterol and 3H‐sitostanol absorption assay (n=4 per genotype). C, Bile acid content in mouse stool in response to cholesterol (n=5 for WT with normal chow, n=5 for Mmp9−/− with normal chow, n=4 for WT with cholesterol, n=5 for Mmp9−/− with cholesterol). *P<0.05 vs WT. †P<0.05 vs normal chow, t test. FPLC indicates fast‐performance liquid chromatography; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MMP, matrix metalloproteinase; VLDL, very low‐density lipoprotein; WT, wild type.
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jah31792-fig-0001: MMP‐9 deficiency is associated with abnormalities in lipid distribution and excretion. A, Triglyceride and cholesterol levels in lipoprotein fractions of plasma separated by FPLC. Traces correspond to pools of plasma from WT and Mmp9−/− mice (n=4 per genotype). Semiquantitative assessment based on peak heights indicates that Mmp9−/− mice have 2.7‐, 4.3‐, 1.5‐, and 1.2‐fold increases in VLDL triglycerides, VLDL cholesterol, LDL cholesterol, and HDL cholesterol, respectively (compared with WT mice). The same volume was injected onto the FPLC. B, Cholesterol absorption measured by radioactive 14C‐cholesterol and 3H‐sitostanol absorption assay (n=4 per genotype). C, Bile acid content in mouse stool in response to cholesterol (n=5 for WT with normal chow, n=5 for Mmp9−/− with normal chow, n=4 for WT with cholesterol, n=5 for Mmp9−/− with cholesterol). *P<0.05 vs WT. †P<0.05 vs normal chow, t test. FPLC indicates fast‐performance liquid chromatography; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MMP, matrix metalloproteinase; VLDL, very low‐density lipoprotein; WT, wild type.

Mentions: Analysis of hepatic lipids revealed further metabolic abnormalities in Mmp9−/− mice including higher levels of triglycerides and cholesteryl esters in the liver of Mmp9−/− mice compared with WT mice, particularly when refed after overnight fasting (Figure S2A). In Mmp9−/− mice, plasma levels of triglycerides and cholesterol were higher in very low‐density lipoproteins and in high‐density lipoproteins than in WT mice (Figure 1A). The higher plasma cholesterol levels in Mmp9−/− mice were not associated with abnormal cholesterol absorption, as demonstrated by the radioactive 14C‐cholesterol and 3H‐sitostanol absorption assay (Figure 1B). Cholesterol excretion in the stool was unchanged in MMP‐9–deficient mice (Figure S2B). There were no statistically significant changes in plasma bile acid content (mean levels were increased on average by 7.4% in Mmp9−/− versus WT mice). The bile acid content, however, was higher in the stool of Mmp9−/− mice fed regular chow than in the stool of WT mice, implying a role for MMP‐9 in the regulation of cholesterol excretion as bile acids (Figure 1C). When the chow was supplemented with 0.15% cholesterol, bile acid excretion remained high in Mmp9−/− mice and was elevated in WT mice, as expected14 (Figure 1C).


Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism
MMP‐9 deficiency is associated with abnormalities in lipid distribution and excretion. A, Triglyceride and cholesterol levels in lipoprotein fractions of plasma separated by FPLC. Traces correspond to pools of plasma from WT and Mmp9−/− mice (n=4 per genotype). Semiquantitative assessment based on peak heights indicates that Mmp9−/− mice have 2.7‐, 4.3‐, 1.5‐, and 1.2‐fold increases in VLDL triglycerides, VLDL cholesterol, LDL cholesterol, and HDL cholesterol, respectively (compared with WT mice). The same volume was injected onto the FPLC. B, Cholesterol absorption measured by radioactive 14C‐cholesterol and 3H‐sitostanol absorption assay (n=4 per genotype). C, Bile acid content in mouse stool in response to cholesterol (n=5 for WT with normal chow, n=5 for Mmp9−/− with normal chow, n=4 for WT with cholesterol, n=5 for Mmp9−/− with cholesterol). *P<0.05 vs WT. †P<0.05 vs normal chow, t test. FPLC indicates fast‐performance liquid chromatography; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MMP, matrix metalloproteinase; VLDL, very low‐density lipoprotein; WT, wild type.
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getmorefigures.php?uid=PMC5121519&req=5

jah31792-fig-0001: MMP‐9 deficiency is associated with abnormalities in lipid distribution and excretion. A, Triglyceride and cholesterol levels in lipoprotein fractions of plasma separated by FPLC. Traces correspond to pools of plasma from WT and Mmp9−/− mice (n=4 per genotype). Semiquantitative assessment based on peak heights indicates that Mmp9−/− mice have 2.7‐, 4.3‐, 1.5‐, and 1.2‐fold increases in VLDL triglycerides, VLDL cholesterol, LDL cholesterol, and HDL cholesterol, respectively (compared with WT mice). The same volume was injected onto the FPLC. B, Cholesterol absorption measured by radioactive 14C‐cholesterol and 3H‐sitostanol absorption assay (n=4 per genotype). C, Bile acid content in mouse stool in response to cholesterol (n=5 for WT with normal chow, n=5 for Mmp9−/− with normal chow, n=4 for WT with cholesterol, n=5 for Mmp9−/− with cholesterol). *P<0.05 vs WT. †P<0.05 vs normal chow, t test. FPLC indicates fast‐performance liquid chromatography; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MMP, matrix metalloproteinase; VLDL, very low‐density lipoprotein; WT, wild type.
Mentions: Analysis of hepatic lipids revealed further metabolic abnormalities in Mmp9−/− mice including higher levels of triglycerides and cholesteryl esters in the liver of Mmp9−/− mice compared with WT mice, particularly when refed after overnight fasting (Figure S2A). In Mmp9−/− mice, plasma levels of triglycerides and cholesterol were higher in very low‐density lipoproteins and in high‐density lipoproteins than in WT mice (Figure 1A). The higher plasma cholesterol levels in Mmp9−/− mice were not associated with abnormal cholesterol absorption, as demonstrated by the radioactive 14C‐cholesterol and 3H‐sitostanol absorption assay (Figure 1B). Cholesterol excretion in the stool was unchanged in MMP‐9–deficient mice (Figure S2B). There were no statistically significant changes in plasma bile acid content (mean levels were increased on average by 7.4% in Mmp9−/− versus WT mice). The bile acid content, however, was higher in the stool of Mmp9−/− mice fed regular chow than in the stool of WT mice, implying a role for MMP‐9 in the regulation of cholesterol excretion as bile acids (Figure 1C). When the chow was supplemented with 0.15% cholesterol, bile acid excretion remained high in Mmp9−/− mice and was elevated in WT mice, as expected14 (Figure 1C).

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.


Related in: MedlinePlus