Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired β-cell function.
Cellular cholesterol homeostasis is important for normal β-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking β-cell ABCA1 have increased islet expression of ABCG1, another cholesterol transporter implicated in β-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in β-cells, mice lacking ABCG1 and β-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and β-cell function were assessed. Lack of both ABCG1 and β-cell ABCA1 resulted in increased fasting glucose levels and a greater impairment in glucose tolerance compared with either ABCG1 deletion or loss of ABCA1 in β-cells alone. In addition, glucose-stimulated insulin secretion was decreased and sterol accumulation increased in islets lacking both transporters compared with those isolated from knockout mice with each gene alone. Combined deficiency of ABCA1 and ABCG1 also resulted in significant islet inflammation as indicated by increased expression of interleukin-1β and macrophage infiltration. Thus, lack of both ABCA1 and ABCG1 induces greater defects in β-cell function than deficiency of either transporter individually. These data suggest that ABCA1 and ABCG1 each make complimentary and important contributions to β-cell function by maintaining islet cholesterol homeostasis in vivo.
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
Janine K
JK
Kruit
Nadeeja
N
Wijesekara
Clara
C
Westwell-Roper
Tim
T
Vanmierlo
Willeke
W
de Haan
Alpana
A
Bhattacharjee
Renmei
R
Tang
Cheryl L
CL
Wellington
Dieter
D
LütJohann
James D
JD
Johnson
Liam R
LR
Brunham
C Bruce
CB
Verchere
Michael R
MR
Hayden
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D018149:Glucose Intolerance / Q000209:etiology; D006706:Homeostasis; D007249:Inflammation / Q000209:etiology*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism*; D008074:Lipoproteins / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051742:Transcription Factor CHOP / Q000502:physiology
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C497250:Ddit3 protein, mouse; D053583:Interleukin-1beta; D008074:Lipoproteins; D051742:Transcription Factor CHOP; D002784:Cholesterol