PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities

Mbikay, Majambu; Sirois, Francine; Mayne, Janice; Wang, Gen-Sheng; Chen, Andrew; Dewpura, Thilina; Prat, Annik; Seidah, Nabil G.; Chretien, Michel; Scott, Fraser W.

doi:10.1016/j.febslet.2009.12.018

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Volume 584, Issue 4 , Pages 701-706, 19 February 2010

PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities

Edited by Robert Barouki

Majambu Mbikay
- 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
- Division of Endocrinology and Metabolism, The Ottawa Hospital, Ottawa, Ontario, Canada
- Corresponding author. Present address: Ottawa Hospital Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9. Fax: +1 613 761 4355.
Francine Sirois
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Janice Mayne
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Gen-Sheng Wang
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Andrew Chen
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Thilina Dewpura
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Annik Prat
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
Michel Chretien
- 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
- Division of Endocrinology and Metabolism, The Ottawa Hospital, Ottawa, Ontario, Canada
Fraser W. Scott
- 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
- Division of Endocrinology and Metabolism, The Ottawa Hospital, Ottawa, Ontario, Canada

Received 19 October 2009; received in revised form 7 December 2009; accepted 11 December 2009. published online 17 December 2009.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver-secreted plasma enzyme, restricts hepatic uptake of low-density lipoprotein (LDL) cholesterol by promoting the degradation of LDL receptors (LDLR). PCSK9 and LDLR are also expressed in insulin-producing pancreatic islet β cells, possibly affecting the function of these cells. Here we show that, compared to control mice, PCSK9-null male mice over 4months of age carried more LDLR and less insulin in their pancreas; they were hypoinsulinemic, hyperglycemic and glucose-intolerant; their islets exhibited signs of malformation, apoptosis and inflammation. Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets.