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J. Biol. Chem., Vol. 283, Issue 15, 9666-9673, April 11, 2008

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Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9^*

Sanae Kourimate^¶1, Cédric Le May, Cédric Langhi, Anne Laure Jarnoux, Khadija Ouguerram^||, Yassine Zaïr^**, Patrick Nguyen, Michel Krempf^||**, Bertrand Cariou^**, and Philippe Costet^¶2

From the INSERM, U915, Nantes, F-44000 France, INSERM, U539, Nantes, F-44000 France, the ^**Clinique d'Endocrinologie et Nutrition, l'Institut du Thorax, CHU de Nantes, Nantes, F-44000 France, the ^||FacultédeMédecine, l'Institut du Thorax, Universitéde Nantes, Nantes, F-44000 France, the ^¶CRNH de Nantes, Nantes, F-44000 France, and the Ecole Nationale Vétérinaire de Nantes, Nantes, F-44000 France

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 PPAR 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 PPAR-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 PPAR activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins.

Received for publication, July 16, 2007 , and in revised form, February 1, 2008.

^* This work was supported in part by the Laboratoires Pierre Fabre, the Agence Nationale de la Recherche (Physiopathologies Humaines 2006 R0651ONS), the Fondation de France, Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques, Programme National de Recherche-Maladies Cardiovasculaires 2006. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Fig. S1.

¹ Supported by the Centre de Recherche en Nutrition Humaine of Nantes and Région Pays de la Loire.

² A Contrat d'Interface INSERM-CHU de Nantes. To whom correspondence should be addressed: INSERM, U915 CHU Hôtel Dieu, 3ENORD, 9, Quai Moncousu, 44000, Nantes, France. Tel.: 33(0)240087533; Fax: 33(0)240087544; E-mail: philippe.costet{at}univ-nantes.fr.

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