MMP‐2 inhibits PCSK9‐induced degradation of the LDL receptor in Hepa1‐c1c7 cells

Wang, Xiang; Berry, Evan; Hernandez-Anzaldo, Samuel; Sun, Difei; Adijiang, Ayinuer; Li, Liang; Zhang, Da Wei; Fernández-Patrón, Carlos

doi:10.1016/j.febslet.2015.01.007

Cited by 14 publications

(11 citation statements)

References 9 publications

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“…These observations demonstrate a potentially important role of MMP‐9 (and the MMP/TIMP system as a whole) in the modulation of cholesterol metabolism. As such, the current research substantially expands previous reports by our groups and other investigators and points to important metabolic actions of MMPs.…”

Section: Discussionsupporting

confidence: 83%

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Hernandez-Anzaldo

Brglez

Hemmeryckx

et al. 2016

JAHA

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BackgroundThe 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 ResultsWe 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.ConclusionsOur 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.

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Section: Discussionsupporting

confidence: 83%

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Hernandez-Anzaldo

Brglez

Hemmeryckx

et al. 2016

JAHA

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“…Recently, matrix metalloproteinase 2 was also found to proteolytically inactivate PCSK9. However, the physiological relevance of this regulatory effect remains to be established [202]. …”

Section: Posttranslational Regulation Of Pcsk9 Activitymentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

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“…Recently, matrix metalloproteinase 2 has been found to proteolytically inactivate PCSK9. However, the physiological relevance of this regulatory effect remains to be established [102]. …”

Section: Expression and Regulation Of Pcsk9 Expressionmentioning

confidence: 99%

PCSK9 targets important for lipid metabolism

Schulz

Schlüter

2017

Clin Res Cardiol Suppl

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Ischemic heart disease is the main cause of death worldwide and it is accelerated by increased low-density lipoprotein (LDL) cholesterol (LDL-C) and/or lipoprotein (a) (Lp(a)) concentrations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) alters both LDL-C and in part Lp(a) concentrations through its ability to induce degradation of the LDL receptor (LDLR). PCSK9, however, has additional targets which are potentially involved in lipid metabolism regulation such as the very low density lipoprotein receptor (VLDL), CD36 (cluster of differentiation 36) and the epithelial cholesterol transporter (NPC1L1) and it affects expression of apolipoprotein B48. The PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Many comorbidities (kidney insufficiency, hypothyreoidism, hyperinsulinemia, inflammation) modify PCSK9 expression and release. Two humanized antibodies directed against extracellular PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics (such as silencing RNA) are already in clinical trials. Their results demonstrate a significant reduction in both LDL-C and Lp(a) concentrations – independent of the concomitant medication – and one of them reduced plaque size in high risk cardiovascular patients; results of two ongoing large clinical endpoints studies are awaited. In this review, we summarize and discuss the recent biological data on PCSK9, the regulation of PCSK9, and finally briefly summarize the data of recent clinical studies in the context of lipid metabolism.

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MMP‐2 inhibits PCSK9‐induced degradation of the LDL receptor in Hepa1‐c1c7 cells

Cited by 14 publications

References 9 publications

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

PCSK9 targets important for lipid metabolism

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