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

Arteriosclerosis, Thrombosis, and Vascular Biology
Damien GarçonCédric Le May

Abstract

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...Continue Reading

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Citations

Dec 29, 2020·Frontiers in Physiology·Klaus-Dieter SchlüterRolf Schreckenberg
May 18, 2021·Frontiers in Cardiovascular Medicine·Yixi ZhaoMin Wu
May 22, 2021·The American Journal of Pathology·Chiara MacchiMassimiliano Ruscica
Jul 20, 2021·Journal of Lipid Research·Moreau FrançoisCedric Le May
Jul 30, 2021·European Heart Journal·Kevin ChemelloGilles Lambert
Oct 10, 2021·Endocrine Reviews·Nabil G Seidah, Annik Prat

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