期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 40, 期 9, 页码 2084-2094出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.120.314194
关键词
diabetes mellitus; intestine; lipid; liver; mice
资金
- Fondation Leducq [13CVD03]
- Pfizer ASPIRE Cardiovascular Competitive Research Grants Program 2015 (Respective roles of intestinal and hepatic PCSK9 on triglyceriderich lipoprotein metabolism)
- Agence Nationale de la Recherche [ANR-16-CE14-0025-01, ANR-16-RHUS-0007]
- Ministere de l'Enseignement superieur, de la Recherche et de l'Innovation
- Agence Nationale de la Recherche (ANR) [ANR-16-CE14-0025] Funding Source: Agence Nationale de la Recherche (ANR)
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-specificPcsk9-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 inPcsk9(+/+)but not inPcsk9(-/-)mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treatedPcsk9(+/+)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.
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