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J. Biol. Chem., Vol. 281, Issue 10, 6211-6218, March 10, 2006

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Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-binding Protein 1c^*

Philippe Costet¹, Bertrand Cariou, Gilles Lambert, Florent Lalanne, Bernard Lardeux, Anne-Laure Jarnoux, Aldo Grefhorst^¶, Bart Staels, and Michel Krempf

From the INSERM, U539, CHU Hôtel Dieu, 44000, Nantes, France, INSERM, U545 and Pasteur Institute of Lille, Faculty of Pharmacy, Lille 2 University, 59019 Lille, France, and the ^¶Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Hospital, 9700RB Groningen, The Netherlands

Familial autosomal dominant hypercholesterolemia is associated with high risk for cardiovascular accidents and is related to mutations in the low density lipoprotein receptor or its ligand apolipoprotein B (apoB). Mutations in a third gene, proprotein convertase subtilisin kexin 9 (PCSK9), were recently associated to this disease. PCSK9 acts as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content and statins, via sterol regulatory element-binding protein (SREBP). Here we investigated the regulation of PCSK9 gene expression during nutritional changes. We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. In contrast PCSK9 expression was restored upon high carbohydrate refeeding. PCSK9 mRNA increased by 4–5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. Moreover, insulin up-regulated hepatic PCSK9 expression in vivo during a hyperinsulinemic-euglycemic clamp in mice. Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression. Liver X receptor agonist T0901317 also regulated PCSK9 expression via this same pathway (a 2-fold increase in PCSK9 mRNA of primary hepatocytes cultured for 24 h in presence of 1 µM T0901317). As our last investigation, we isolated PCSK9 proximal promoter and verified the functionality of a SREBP-1c responsive element located from 335 bp to 355 bp upstream of the ATG. Together, these results show that PCSK9 expression is regulated by nutritional status and insulinemia.

Received for publication, August 4, 2005 , and in revised form, January 3, 2006.

^* This work was supported by Fondation de France, Centre de Recherche en Nutrition Humaine de Nantes and Pierre Fabre. 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.

¹ To whom correspondence should be addressed: INSERM, U539; CHU Hôtel Dieu, 3eme étage Nord, 1 Place Alexis Ricordeau, 44093 Nantes cedex, France. Tel.: 332-40-08-75-33; Fax: 332-40-08-75-44; E-mail: philippe.costet{at}univ-nantes.fr.

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