title: Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules.
abstract: OBJECTIVE
  The ATP-binding cassette transporter A1 (ABCA1) is essential for normal insulin secretion from β-cells. The aim of this study was to elucidate the mechanisms underlying the impaired insulin secretion in islets lacking β-cell ABCA1.
  
  
  METHODS
  Calcium imaging, patch clamp, and membrane capacitance were used to assess the effect of ABCA1 deficiency on calcium flux, ion channel function, and exocytosis in islet cells. Electron microscopy was used to analyze β-cell ultrastructure. The quantity and distribution of proteins involved in insulin-granule exocytosis were also investigated.
  
  
  RESULTS
  We show that a lack of β-cell ABCA1 results in impaired depolarization-induced exocytotic fusion of insulin granules. We observed disturbances in membrane microdomain organization and Golgi and insulin granule morphology in β-cells as well as elevated fasting plasma proinsulin levels in mice in the absence of β-cell ABCA1. Acute cholesterol depletion rescued the exocytotic defect in β-cells lacking ABCA1, indicating that elevated islet cholesterol accumulation directly impairs granule fusion and insulin secretion.
  
  
  CONCLUSIONS
  Our data highlight a crucial role of ABCA1 and cellular cholesterol in β-cells that is necessary for regulated insulin granule fusion events. These data suggest that abnormalities of cholesterol metabolism may contribute to the impaired β-cell function in diabetes.
authors: Departments of Medical Genetics, Centre for Molecular Medicine, and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Janine K
authors: JK
authors: Kruit
authors: Nadeeja
authors: N
authors: Wijesekara
authors: Jocelyn E Manning
authors: JE
authors: Fox
authors: Xiao-Qing
authors: XQ
authors: Dai
authors: Liam R
authors: LR
authors: Brunham
authors: Gavin J
authors: GJ
authors: Searle
authors: Garry P
authors: GP
authors: Morgan
authors: Adam J
authors: AJ
authors: Costin
authors: Renmei
authors: R
authors: Tang
authors: Alpana
authors: A
authors: Bhattacharjee
authors: James D
authors: JD
authors: Johnson
authors: Peter E
authors: PE
authors: Light
authors: Brad J
authors: BJ
authors: Marsh
authors: Patrick E
authors: PE
authors: Macdonald
authors: C Bruce
authors: CB
authors: Verchere
authors: Michael R
authors: MR
authors: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004594:Electrophysiology; D005089:Exocytosis / Q000235:genetics / Q000502:physiology*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D015220:Calcium Channels; D007328:Insulin; D002784:Cholesterol; D002118:Calcium