Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL/6 mice 性别与西方饮食对CSK9基因缺陷的PC57BL/6老龄小鼠的脂质以及葡萄糖内稳态的不同影响

Background Proprotein convertase subtilisin/kexin-type 9 (PCSK9) downregulates clearance of plasma cholesterol by liver. Its inactivation increases this clearance, reducing cardiovascular risk. However, a lack of PCSK9 could also lead to cholesterol accumulation in pancreatic islet beta cells, impairing insulin secretion. We reported earlier that 4-month-old male PCSK9-deficient (KO) C57BL/6 mice were hyperglycemic and insulin-insufficient relative to their wild-type (WT) counterparts. Here, we examined how gender and diet affect lipid and glucose homeostasis in these mice at 8 months of age. Methods After being fed a normal diet or a Western diet for over 6 months, KO mice were compared with same-gender WT mice for fasting plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and insulin; for glucose disposal and glucose-stimulated insulin secretion (GSIS); and for pancreatic islet morphology. Results A. Females: On normal diet, KO mice showed lower plasma TC, HDL-C, and LDL-C, higher plasma glucose, and normal glucose disposal despite impaired GSIS. On Western diet, they showed comparable plasma TC and HDL-C, but lower LDL-C, higher plasma glucose, and normal glucose disposal despite impaired GSIS. B. Males: On normal and Western diets, KO mice showed lower plasma TC, HDL-C, and LDL-C, similarly elevated plasma glucose, glucose intolerance, and impaired GSIS. C. Both: KO mice on either diet showed pancreatic islet dysmorphism, with larger, possibly immature secretory granules. Conclusions Lower LDL-C and impaired GSIS are two major phenotypes in aged PCSK9-deficient C57BL/6 mice. These phenotypes are modulated by gender and diet. 摘要 背景：前蛋白转化酶枯草溶菌素9（Proprotein convertase subtilisin/kexin-type 9，PCSK9）可以下调肝脏对血浆胆固醇的清除。它的灭活可以增加这种清除，减少心血管风险。然而，缺乏PCSK9可导致胆固醇在胰岛β细胞中蓄积，减少胰岛素分泌。我们曾经报告了4月龄雄性PCSK9基因缺陷（KO）的C57BL/6小鼠与它们的野生型对照组相比有高血糖症并且缺乏胰岛素。在这些小鼠8月龄的时候我们调查了性别与饮食对脂质以及葡萄糖内稳态的影响。 方法：经过6个月的正常饮食或者西方饮食饲养之后，将KO小鼠与同性别的野生型小鼠相比较，对比了空腹血浆中的总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、葡萄糖以及胰岛素水平；还对比了葡萄糖处理与葡萄糖刺激的胰岛素分泌（glucose-stimulated insulin secretion，GSIS）以及胰岛形态学。 结果： A. 雌性：在正常饮食组中，发现KO小鼠血浆中的TC、HDL-C以及LDL-C更低，血糖更高，尽管GSIS受损但是葡萄糖的处理能力仍然正常。在西方饮食组中，发现它们的血浆TC和HDL-C水平相类似，但是LDL-C更低，血糖更高，尽管GSIS受损但是葡萄糖的处理能力仍然正常。B. 雄性：在正常饮食以及西方饮食组中，发现KO小鼠的血浆TC、HDL-C以及LDL-C都更低，而血糖升高幅度、葡萄糖耐量异常以及GSIS受损都相类似。C. 两种性别：发现KO小鼠在任何一个饮食组中都有胰岛畸形，并且具有可能是不成熟的大分泌颗粒。 结论：在PCSK9基因缺陷的C57BL/6老龄小鼠中，两种主要的表现型是LDL-C降低与GSIS受损。这些表现型受到了性别与饮食的影响。