Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France.
Université de Nantes, CRNH Ouest, Inra UMR 1280 PhAN, Nantes, France; L'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
Atherosclerosis. 2021 Jun;326:47-55. doi: 10.1016/j.atherosclerosis.2021.03.044. Epub 2021 Apr 20.
Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) is an endogenous inhibitor of the LDL receptor (LDLR). Mendelian randomization studies suggest that PCSK9 deficiency increases diabetes risk, but the underlying mechanisms remain unknown. The aim of our study was to investigate whether PCSK9 or its inhibition may modulate beta cell function.
We assessed PCSK9 and insulin colocalization in human pancreatic sections by epifluorescent and confocal microscopy. We also investigated the expression and the function of PCSK9 in the human EndoC-βH1 beta cell line, by ELISA and flow cytometry, respectively. PCSK9 was inhibited with Alirocumab or siRNA. LDLR expression and LDL uptake were assessed by flow cytometry.
PCSK9 was expressed and secreted from beta cells isolated from human pancreas as well as from EndoC-βH1 cells. PCSK9 secretion was enhanced by statin treatment. Recombinant PCSK9 decreased LDLR abundance at the surface of these cells, an effect abrogated by Alirocumab. Alirocumab as well as PCSK9 silencing increased LDLR expression at the surface of EndoC-βH1 cells. Neither exogenous PCSK9, nor Alirocumab, nor PCSK9 silencing significantly altered glucose-stimulated insulin secretion (GSIS) from these cells. High-low density lipoproteins (LDL) concentrations decreased GSIS, but the addition of PCSK9 or its inhibition did not modulate this phenomenon.
While PCSK9 regulates LDLR abundance in beta cells, inhibition of exogenous or endogenous PCSK9 does not appear to significantly impact insulin secretion. This is reassuring for the safety of PCSK9 inhibitors in terms of beta cell function.
前蛋白转化酶枯草溶菌素 9（PCSK9）是 LDL 受体（LDLR）的内源性抑制剂。孟德尔随机化研究表明，PCSK9 缺乏会增加糖尿病风险，但潜在机制尚不清楚。本研究旨在探讨 PCSK9 或其抑制是否可能调节β细胞功能。
我们通过荧光显微镜和共聚焦显微镜评估人胰腺切片中 PCSK9 和胰岛素的共定位。我们还通过 ELISA 和流式细胞术分别研究了 PCSK9 在人 EndoC-βH1β细胞系中的表达和功能。用 Alirocumab 或 siRNA 抑制 PCSK9。通过流式细胞术评估 LDLR 表达和 LDL 摄取。
PCSK9 从人胰腺分离的β细胞和 EndoC-βH1 细胞中表达和分泌。他汀类药物治疗增强了 PCSK9 的分泌。重组 PCSK9 减少了这些细胞表面 LDLR 的丰度，Alirocumab 可消除这种作用。Alirocumab 以及 PCSK9 沉默增加了 EndoC-βH1 细胞表面的 LDLR 表达。外源性 PCSK9、Alirocumab 或 PCSK9 沉默均未显著改变这些细胞的葡萄糖刺激胰岛素分泌（GSIS）。高低密度脂蛋白（LDL）浓度降低了 GSIS，但添加 PCSK9 或其抑制物并未调节这种现象。
虽然 PCSK9 调节β细胞中的 LDLR 丰度，但抑制外源性或内源性 PCSK9 似乎不会显著影响胰岛素分泌。这对于 PCSK9 抑制剂在β细胞功能方面的安全性来说是令人安心的。
