Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Laboratory of Functional Endoproteolysis, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
J Diabetes. 2015 Jan;7(1):74-84. doi: 10.1111/1753-0407.12139. Epub 2014 Mar 27.
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.
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.
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.
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.
前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）可下调肝脏对血浆胆固醇的清除率。其失活会增加这种清除率，从而降低心血管风险。然而，PCSK9 的缺乏也可能导致胰岛β细胞中胆固醇的积累，从而损害胰岛素的分泌。我们之前报道过，4 月龄的雄性 PCSK9 缺陷（KO）C57BL/6 小鼠相对于野生型（WT）对照表现为高血糖和胰岛素不足。在这里，我们研究了在 8 月龄时，性别和饮食如何影响这些小鼠的脂质和葡萄糖稳态。
在正常饮食或西方饮食喂养超过 6 个月后，将 KO 小鼠与同性别 WT 小鼠进行比较，检测其空腹时的总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、血糖和胰岛素水平；葡萄糖摄取和葡萄糖刺激胰岛素分泌（GSIS）；以及胰岛形态。
A. 雌性：在正常饮食时，KO 小鼠的血浆 TC、HDL-C 和 LDL-C 较低，血糖较高，尽管 GSIS 受损，但葡萄糖摄取正常。在西方饮食时，它们的血浆 TC 和 HDL-C 相当，但 LDL-C 较低，血糖较高，葡萄糖摄取正常，尽管 GSIS 受损。B. 雄性：在正常和西方饮食时，KO 小鼠的血浆 TC、HDL-C 和 LDL-C 较低，血糖同样升高，葡萄糖耐量受损，GSIS 受损。C. 两者：两种饮食的 KO 小鼠均表现出胰岛形态异常，可能存在较大、不成熟的分泌颗粒。
在年老的 PCSK9 缺陷 C57BL/6 小鼠中，较低的 LDL-C 和受损的 GSIS 是两个主要表型。这些表型受性别和饮食的调节。
