Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules

Kruit, Janine K., Wijesekara, Nadeeja, Fox, Jocelyn E., Dai, Xiao-Qing, Brunham, Liam R., Searle, Gavin J., Morgan, Garry P., Costin, Adam J., Tang, Renmei, Bhattacharjee, Alpana, Johnson, James D., Light, Peter E., Marsh, Brad J., Macdonald, Patrick E., Verchere, C. Bruce and Hayden, Michael R. (2011) Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules. Diabetes, 60 12: 3186-3196. doi:10.2337/db11-0081

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Author Kruit, Janine K.
Wijesekara, Nadeeja
Fox, Jocelyn E.
Dai, Xiao-Qing
Brunham, Liam R.
Searle, Gavin J.
Morgan, Garry P.
Costin, Adam J.
Tang, Renmei
Bhattacharjee, Alpana
Johnson, James D.
Light, Peter E.
Marsh, Brad J.
Macdonald, Patrick E.
Verchere, C. Bruce
Hayden, Michael R.
Title Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules
Formatted title
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
Publication date 2011-10-12
Sub-type Article (original research)
DOI 10.2337/db11-0081
Volume 60
Issue 12
Start page 3186
End page 3196
Total pages 11
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Collection year 2012
Language eng
Formatted 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.

Research and Design 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.

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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 17 Oct 2011, 22:33:58 EST by Brad Marsh on behalf of School of Chemistry & Molecular Biosciences