Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with familial autosomal dominant hypercholesterolemia and is a natural inhibitor of the LDL receptor (LDLr). PCSK9 is degraded by other proprotein convertases: PC5/6A and furin. Both PCSK9 and the LDLr are up-regulated by the hypocholesterolemic statins. Thus, inhibitors or repressors of PCSK9 should amplify their beneficial effects. In the present study, we showed that PPARalpha activation counteracts PCSK9 induction by statins by repressing PCSK9 promoter activity and by increasing PC5/6A and furin expression. Quantification of mRNA and protein levels showed that various fibrates decreased PCSK9 and increased PC5/6A and furin expression. Fenofibric acid (FA) reduced PCSK9 protein content in immortalized human hepatocytes (IHH) as well as its cellular secretion. FA suppressed PCSK9 induction by statins or by the liver X receptor agonist TO901317. PCSK9 repression is occurring at the promoter level. We showed that PC5/6A and furin fibrate-mediated up-regulation is PPARalpha-dependent. As a functional test, we observed that FA increased by 30% the effect of pravastatin on the LDLr activity in vitro. In conclusion, fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARalpha activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2008 |
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| Erschienen: |
2008 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:283 |
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| Enthalten in: |
The Journal of biological chemistry - 283(2008), 15 vom: 11. Apr., Seite 9666-73 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kourimate, Sanae [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.05.2008 Date Revised 22.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.M705831200 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM177340894 |
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| 041 | |a eng | ||
| 100 | 1 | |a Kourimate, Sanae |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9 |
| 264 | 1 | |c 2008 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 28.05.2008 | ||
| 500 | |a Date Revised 22.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with familial autosomal dominant hypercholesterolemia and is a natural inhibitor of the LDL receptor (LDLr). PCSK9 is degraded by other proprotein convertases: PC5/6A and furin. Both PCSK9 and the LDLr are up-regulated by the hypocholesterolemic statins. Thus, inhibitors or repressors of PCSK9 should amplify their beneficial effects. In the present study, we showed that PPARalpha activation counteracts PCSK9 induction by statins by repressing PCSK9 promoter activity and by increasing PC5/6A and furin expression. Quantification of mRNA and protein levels showed that various fibrates decreased PCSK9 and increased PC5/6A and furin expression. Fenofibric acid (FA) reduced PCSK9 protein content in immortalized human hepatocytes (IHH) as well as its cellular secretion. FA suppressed PCSK9 induction by statins or by the liver X receptor agonist TO901317. PCSK9 repression is occurring at the promoter level. We showed that PC5/6A and furin fibrate-mediated up-regulation is PPARalpha-dependent. As a functional test, we observed that FA increased by 30% the effect of pravastatin on the LDLr activity in vitro. In conclusion, fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARalpha activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anticholesteremic Agents |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Hydrocarbons, Fluorinated |2 NLM | |
| 650 | 7 | |a Liver X Receptors |2 NLM | |
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| 650 | 7 | |a Clofibric Acid |2 NLM | |
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| 650 | 7 | |a Serine Endopeptidases |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a FURIN protein, human |2 NLM | |
| 650 | 7 | |a EC 3.4.21.75 |2 NLM | |
| 650 | 7 | |a Furin |2 NLM | |
| 650 | 7 | |a EC 3.4.21.75 |2 NLM | |
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| 700 | 1 | |a Le May, Cédric |e verfasserin |4 aut | |
| 700 | 1 | |a Langhi, Cédric |e verfasserin |4 aut | |
| 700 | 1 | |a Jarnoux, Anne Laure |e verfasserin |4 aut | |
| 700 | 1 | |a Ouguerram, Khadija |e verfasserin |4 aut | |
| 700 | 1 | |a Zaïr, Yassine |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Krempf, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Cariou, Bertrand |e verfasserin |4 aut | |
| 700 | 1 | |a Costet, Philippe |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:283 |g year:2008 |g number:15 |g day:11 |g month:04 |g pages:9666-73 |
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