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Diabetologia. 2016 Jun;59(6):1242-6. doi: 10.1007/s00125-016-3907-6. Epub 2016 Mar 12.

ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice.

Author information

1
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
2
Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
3
Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
4
Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. bverchere@cfri.ca.
5
Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada. bverchere@cfri.ca.

Abstract

AIMS/HYPOTHESIS:

Islet amyloid, a pathological feature of type 2 diabetes, forms from the aggregation of islet amyloid polypeptide (IAPP), a beta cell peptide that is produced and co-secreted with insulin. Cholesterol regulates amyloid-β processing, deposition and clearance, promoting amyloidogenesis in the brain. ATP-binding cassette transporter 1 (ABCA1) is a cholesterol efflux transporter that when absent increases and when overexpressed reduces brain amyloid-β deposition in mouse models of Alzheimer's disease. We examined whether alterations in ABCA1 expression and islet cholesterol content could also modulate islet amyloidogenesis.

METHODS:

Thioflavin S staining for amyloid was performed in islets isolated from mice with beta cell expression of human IAPP (hIAPP (Tg/o)) and cultured for 8 days following cholesterol loading, microRNA-33 overexpression (to reduce ABCA1 expression) or palmitate treatment in the presence or absence of ABCA1 overexpression or mevastatin treatment (to reduce cholesterol synthesis). hIAPP (Tg/o) mice were crossed with beta cell-specific Abca1-knockout mice (hIAPP (Tg/o) Abca1 (βKO)) and glucose tolerance and amyloid formation were assessed.

RESULTS:

Cholesterol loading and microRNA-33-induced reduction in islet ABCA1 expression increased Thioflavin S-positive amyloid in hIAPP (Tg/o) islets. Palmitate treatment also increased amyloid formation and this was reduced by both ABCA1 overexpression and mevastatin treatment. hIAPP (Tg/o) Abca1 (βKO) mice had increased islet cholesterol, accompanied by fasting hyperglycaemia, glucose intolerance, impaired in vivo insulin secretion and an increased islet proinsulin:insulin ratio. Amyloid area was increased in cultured hIAPP (Tg/o) Abca1 (βKO) islets compared with hIAPP (Tg/o) controls.

CONCLUSIONS/INTERPRETATION:

These data suggest that elevations in islet cholesterol may lead to increases in IAPP aggregation and islet amyloid formation, further worsening beta cell function and glucose homeostasis.

KEYWORDS:

ABCA1; Cholesterol; IAPP; Islet amyloid

PMID:
26970755
DOI:
10.1007/s00125-016-3907-6
[Indexed for MEDLINE]

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