title: Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL/6 mice CSK9PC57BL/6.
abstract: 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.
authors.affiliation: 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.
authors.forename: Majambu
authors.initials: M
authors.lastname: Mbikay
authors.forename: Francine
authors.initials: F
authors.lastname: Sirois
authors.forename: Charles
authors.initials: C
authors.lastname: Gyamera-Acheampong
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Rippstein
authors.forename: Andrew
authors.initials: A
authors.lastname: Chen
authors.forename: Janice
authors.initials: J
authors.lastname: Mayne
authors.forename: Fraser W
authors.initials: FW
authors.lastname: Scott
authors.forename: Michel
authors.initials: M
authors.lastname: Chrétien
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D066273:Diet, Western; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000502:physiology*; D012697:Serine Endopeptidases / Q000502:physiology*; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: cholesterol; insulin secretion; lipoproteins; pancreatic islets; proprotein convertases; 关键词：胆固醇，胰岛素分泌，脂蛋白，胰岛，前蛋白转化酶