title: ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nadeeja
authors.initials: N
authors.lastname: Wijesekara
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Achint
authors.initials: A
authors.lastname: Kaur
authors.affiliation: Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: Westwell-Roper
authors.affiliation: Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dominika
authors.initials: D
authors.lastname: Nackiewicz
authors.affiliation: Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Galina
authors.initials: G
authors.lastname: Soukhatcheva
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: 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.|Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada. bverchere@cfri.ca.
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000172:deficiency* / Q000235:genetics; D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D051381:Rats
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000682:Amyloid; D002784:Cholesterol; D058228:Islet Amyloid Polypeptide; D008148:Lovastatin; D035683:MicroRNAs; D010168:Palmitates; C577833:Abca1 protein, mouse; C550417:Mirn33 microRNA, mouse; C012258:mevastatin
keywords: ABCA1; Cholesterol; IAPP; Islet amyloid