title: Hepatic ABCA1 expression improves β-cell function and glucose tolerance.
abstract: Low HDL is a risk factor for the development of type 2 diabetes. Hepatic ABCA1 is the rate-limiting protein in HDL biogenesis, and mice lacking hepatic ABCA1 (ABCA1(-l/-l)) have very low plasma HDL concentrations. To investigate the role of hepatic ABCA1 in glucose tolerance and β-cell function, we used ABCA1(-l/-l) mice, which showed impaired glucose tolerance without changes in insulin sensitivity. Insulin secretion was reduced following glucose gavage. Ex vivo, glucose stimulated insulin secretion from β-cells from wild-type (WT) and ABCA1(-l/-l) mice was similar. Insulin secretion was, however, reduced upon addition of ABCA1(-l/-l) serum to the medium compared with WT serum, whereas islets lacking β-cell ABCA1 were not affected differently by ABCA1(-l/-l) or WT serum. After high-fat feeding, WT and ABCA1(-l/-l) mice showed no difference in glucose tolerance or insulin secretion, and serum from ABCA1(-l/-l) and WT mice fed a high-fat diet did not affect insulin secretion differently. We conclude that hepatic ABCA1 improves glucose tolerance by improving β-cell function through both HDL production and interaction with β-cell ABCA1. The beneficial effect of hepatic ABCA1 is decreased under metabolic stress. Increasing hepatic ABCA1 may represent a novel therapeutic strategy for improving glucose homeostasis in diabetes.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Willeke
authors.initials: W
authors.lastname: de Haan
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Karasinska
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Piers
authors.initials: P
authors.lastname: Ruddle
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada mrh@cmmt.ubc.ca.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D064286:ATP Binding Cassette Transporter 1; D005947:Glucose; D007328:Insulin; D008075:Lipoproteins, HDL; C577833:Abca1 protein, mouse