Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Arteriosclerosis, Thrombosis, and Vascular Biology Année : 2020

Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice

Résumé

Objective: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9-deficient (i-Pcsk9-/-) mouse model. PPL was measured in i-Pcsk9-/- as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9-/- mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr-/- mice. In contrast, i-Pcsk9-/- mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9+/+ but not in Pcsk9-/- mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9+/+ mice. Conclusions: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.
Fichier principal
Vignette du fichier
2020 - Garcon D. et al - iPCSK9 KO - ATVB 2020.pdf (1.44 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03012708 , version 1 (24-11-2022)

Identifiants

Citer

Damien Garçon, François Moreau, Audrey Ayer, Wieneke Dijk, Xavier Prieur, et al.. Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 2020, 40 (9), pp.2084-2094. ⟨10.1161/ATVBAHA.120.314194⟩. ⟨hal-03012708⟩
24 Consultations
10 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More