Department of Nutrition, Montreal Diabetes Research Center, CRCHUM, Montreal, Canada.
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), Montreal, Canada.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Aug;1866(8):158968. doi: 10.1016/j.bbalip.2021.158968. Epub 2021 May 13.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in cholesterol homeostasis by promoting the degradation of the LDL receptor (LDLR). PCSK9 loss-of-function mutations are associated with increased fasting plasma glucose levels and slightly elevated risk of type 2-diabetes. Considering the known detrimental effects of cholesterol accumulation in β-cell, and the widespread use of PCSK9 inhibitors to treat hypercholesterolemia, it is important to gain insight into the role of pancreatic PCSK9 in glucose homeostasis and β-cell function. We generated the first β-cell-specific KO of PCSK9 (βKO). PCSK9 mRNA and protein expression were reduced by 48% and 78% in βKO islets, respectively, indicating that β-cells constitute a major site of PCSK9 expression. In islets, loss of β-cell PCSK9 resulted in unchanged LDLR protein levels, but reduced LDLR mRNA, indicating that cholesterol internalization is enhanced and that β-cell PCSK9 promotes LDLR degradation. In contrast, whole body PCSK9 KO mice exhibited 2-fold higher LDLR protein levels in islets and a stable expression of cholesterogenic genes. Whole body KO and βKO mice presented normal glucose tolerance, insulin release in response to glucose load and insulin sensitivity. Ex vivo glucose-stimulated insulin secretion in presence or absence of fatty acids was similar in WT and KO islets. Like KO mice, individuals carrying loss-of-function PCSK9 variants may be protected from cholesterol-induced toxicity due to reduced circulating cholesterol levels. Using both whole body KO or βKO models, our data demonstrate that PCSK9 deletion in mouse does not have any toxic effect on β-cell function and glucose homeostasis.
前蛋白转化酶枯草溶菌素/胰凝乳蛋白酶 9（PCSK9）通过促进 LDL 受体（LDLR）的降解，在胆固醇稳态中发挥重要作用。PCSK9 功能丧失性突变与空腹血糖水平升高和 2 型糖尿病风险略有升高有关。考虑到胆固醇在β细胞中积累的已知有害影响，以及广泛使用 PCSK9 抑制剂来治疗高胆固醇血症，了解胰腺 PCSK9 在葡萄糖稳态和β细胞功能中的作用非常重要。我们生成了第一个β细胞特异性 PCSK9（βKO）敲除小鼠。βKO 胰岛中 PCSK9 mRNA 和蛋白表达分别降低了 48%和 78%，表明β细胞是 PCSK9 表达的主要部位。在胰岛中，β细胞 PCSK9 的缺失导致 LDLR 蛋白水平不变，但 LDLR mRNA 减少，表明胆固醇内化增强，β细胞 PCSK9 促进 LDLR 降解。相比之下，全身 PCSK9 KO 小鼠的胰岛 LDLR 蛋白水平增加了 2 倍，胆固醇生成基因的表达稳定。全身 KO 和βKO 小鼠的葡萄糖耐量正常，葡萄糖负荷时胰岛素释放和胰岛素敏感性正常。在存在或不存在脂肪酸的情况下，WT 和 KO 胰岛的体外葡萄糖刺激的胰岛素分泌相似。像 KO 小鼠一样，携带 PCSK9 功能丧失性变异的个体可能由于循环胆固醇水平降低而免受胆固醇诱导的毒性。使用全身 KO 或βKO 模型，我们的数据表明，PCSK9 在小鼠中的缺失对β细胞功能和葡萄糖稳态没有任何毒性作用。
