Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anticholesteremic Agents / pharmacology*
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Anticholesteremic Agents / therapeutic use
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Cell Line, Tumor
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Clofibric Acid / pharmacology*
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Clofibric Acid / therapeutic use
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DNA-Binding Proteins / metabolism
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Fenofibrate / analogs & derivatives
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Fenofibrate / pharmacology
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Furin / biosynthesis
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Furin / genetics
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Gene Expression Regulation, Enzymologic / drug effects*
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Gene Expression Regulation, Enzymologic / genetics
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Hepatocytes / enzymology*
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Humans
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Hydrocarbons, Fluorinated
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Hyperlipoproteinemia Type II / drug therapy
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Hyperlipoproteinemia Type II / enzymology
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Hyperlipoproteinemia Type II / genetics
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Lipid Metabolism / drug effects
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Lipid Metabolism / genetics
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Liver X Receptors
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Orphan Nuclear Receptors
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PPAR alpha / genetics
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PPAR alpha / metabolism*
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Pravastatin / pharmacology
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Pravastatin / therapeutic use
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Promoter Regions, Genetic / genetics
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Proprotein Convertase 5 / biosynthesis
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Proprotein Convertase 5 / genetics
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Proprotein Convertase 9
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Proprotein Convertases
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Serine Endopeptidases / biosynthesis*
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Serine Endopeptidases / genetics
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Sulfonamides / pharmacology
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Up-Regulation / drug effects
Substances
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Anticholesteremic Agents
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DNA-Binding Proteins
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Hydrocarbons, Fluorinated
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Liver X Receptors
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Orphan Nuclear Receptors
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PPAR alpha
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Receptors, Cytoplasmic and Nuclear
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Receptors, LDL
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Sulfonamides
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T0901317
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Clofibric Acid
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fenofibric acid
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PCSK9 protein, human
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Proprotein Convertase 5
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Proprotein Convertase 9
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Proprotein Convertases
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Serine Endopeptidases
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FURIN protein, human
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Furin
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Pravastatin
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Fenofibrate