PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke
Notice bibliographique
Résumé
The proprotein convertase PCSK9 ( 1 ) is the third gene involved in autosomal dominant familial hypercholesterolemia ( Gain-of-function PCSK9 mutations result in increased levels of plasma low density lipoprotein (LDL) cholesterol ( 2-4 ). In contrast, gene disruption ( 5, 6 ) and loss-of-function mutations in PCSK9 ( 3, 7 ) prevent the degradation of the LDL receptor (LDLR), resulting in a higher clearance of plasma LDL-cholesterol. These seminal fi ndings led to the development of therapies based on PCSK9 inhibition/silencing for the treatment of hypercholesterolemia ( 8, 9 ). Although liver LDLR protein levels are reduced in mice injected with PCSK9 ( 10, 11 ) or overexpressing PCSK9 in hepatocytes ( 6 ), high quantities of PCSK9 can also downregulate LDLR protein levels in extrahepatic tissues such as the lung, adipose, and kidney ( 12, 13 ), suggesting that endogenous circulating PCSK9 that originates from hepatocytes ( 6, 13 ) may downregulate LDLR protein in others tissues. At adulthood, PCSK9 is highly expressed in liver and is also abundant in the small intestine, as well as in the kidney and brain throughout embryonic development ( 1 ). In mouse brain, PCSK9 is transiently expressed in the telencephalon [maximal at embryonic day (E)12.5] and cerebellum [from E17.5 to postnatal day (P)19] ( 1 ). At adulthood, it is only significantly expressed in the rostral extension of the olfactory peduncle (RE-OP) ( 1 ). In addition, transgenic mice Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in cholesterol homeostasis through enhanced degradation of the LDL receptor (LDLR) in liver. As novel inhibitors/silencers of PCSK9 are now being tested in clinical trials to treat hypercholesterolemia, it is crucial to defi ne the physiological consequences of the lack of PCSK9 in various organs. LDLR regulation by PCSK9 has not been extensively described during mouse brain development and injury. Herein, we show that PCSK9 and LDLR are co-expressed in mouse brain during development and at adulthood. Although the protein levels of LDLR and apolipoprotein E (apoE) in the adult brain of Pcsk9 / mice are similar to those of wild-type (WT) mice, LDLR levels increased and were accompanied by a reduction of apoE levels during development. This suggests that the upregulation of LDLR protein levels in Pcsk9 / mice enhances apoE degradation. Upon ischemic stroke, PCSK9 was expressed in the dentate gyrus between 24 h and 72 h following brain reperfusion. Although mouse behavior and lesion volume were similar, LDLR protein levels dropped 2-fold less in the Pcsk9 / -lesioned hippocampus, without affecting apoE levels and neurogenesis. Thus, PCSK9 downregulates LDLR levels during brain development and following transient ischemic stroke in adult mice. -
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,006 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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