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

• DOI: 10.1161/atvbaha.120.314194
• Publication Date: 2020-07-16T09:00:28Z
• Authors: Damien Garçon; François Moreau; Audrey Ayer; Wieneke Dijk; Xavier Prieur; Lucie Arnaud; Anna Roubtsova; Nabil Seidah; Annik Prat; Bertrand Cariou; Cédric Le May
• Keywords: Male; mice; 610; Hyperlipidemias; liver; Antibodies, Monoclonal, Humanized; Diabetes Mellitus, Experimental; 03 medical and health sciences; 0302 clinical medicine; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; lipid; [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]; Animals; intestine; Hypolipidemic Agents; Mice, Knockout; PCSK9 Inhibitors; [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology; [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism; Postprandial Period; Lipids; 3. Good health; Intestines; Mice, Inbred C57BL; Diabetes Mellitus, Type 2; Receptors, LDL; diabetes mellitus; Proprotein Convertase 9

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.