Abstract
Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by β-cells. The reasons for β-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in β-cells. Mice with specific inactivation of Abca1 in β-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator–activated receptor-γ, which upregulates Abca1 in β-cells, requires β-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in β-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to β-cell dysfunction in type 2 diabetes.
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References
Perley, M.J. & Kipnis, D.M. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. J. Clin. Invest. 46, 1954–1962 (1967).
Unger, R.H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44, 863–870 (1995).
Zhou, Y.P. & Grill, V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J. Clin. Endocrinol. Metab. 80, 1584–1590 (1995).
Shimabukuro, M., Zhou, Y.T., Levi, M. & Unger, R.H. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc. Natl. Acad. Sci. USA 95, 2498–2502 (1998).
Oram, J.F. & Lawn, R.M. Abca1. The gatekeeper for eliminating excess tissue cholesterol. J. Lipid Res. 42, 1173–1179 (2001).
McNeish, J. et al. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc. Natl. Acad. Sci. USA 97, 4245–4250 (2000).
Langmann, T. et al. Molecular cloning of the human ATP-binding cassette transporter 1(hABC1): evidence for sterol-dependent regulation in macrophages. Biochem. Biophys. Res. Commun. 257, 29–33 (1999).
Timmins, J.M. et al. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J. Clin. Invest. 115, 1333–1342 (2005).
Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 274, 305–315 (1999).
Brunham, L.R. et al. Intestinal Abca1 directly contributes to HDL biogenesis in vivo. J. Clin. Invest. 116, 1052–1062 (2006).
Goldstein, J.L., DeBose-Boyd, R.A. & Brown, M.S. Protein sensors for membrane sterols. Cell 124, 35–46 (2006).
Kennedy, M.A. et al. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 1, 121–131 (2005).
Xia, F. et al. Disruption of pancreatic beta-cell lipid rafts modifies Kv2.1 channel gating and insulin exocytosis. J. Biol. Chem. 279, 24685–24691 (2004).
Chinetti, G. et al. PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the Abca1 pathway. Nat. Med. 7, 53–58 (2001).
Eckel, R.H., Grundy, S.M. & Zimmet, P.Z. The metabolic syndrome. Lancet 365, 1415–1428 (2005).
Roehrich, M.E. et al. Insulin-secreting beta cell dysfunction induced by human lipoproteins. J. Biol. Chem. 278, 18368–18375 (2003).
Cnop, M., Hannaert, J.C., Grupping, A.Y. & Pipeleers, D.G. Low density lipoprotein can cause death of islet beta-cells by its cellular uptake and oxidative modification. Endocrinology 143, 3449–3453 (2002).
Grupping, A.Y. et al. Low density lipoprotein binding and uptake by human and rat islet beta cells. Endocrinology 138, 4064–4068 (1997).
Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).
Brunham, L.R., Singaraja, R.R. & Hayden, M.R. Variations on a gene: rare and common variants in Abca1 and their impact on HDL cholesterol levels and atherosclerosis. Annu. Rev. Nutr. 26, 105–129 (2006).
Daimon, M. et al. Association of the Abca1 gene polymorphisms with type 2 DM in a Japanese population. Biochem. Biophys. Res. Commun. 329, 205–210 (2005).
Cnop, M. et al. Endocytosis of low-density lipoprotein by human pancreatic beta cells and uptake in lipid-storing vesicles, which increase with age. Am. J. Pathol. 156, 237–244 (2000).
Henquin, J.C. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49, 1751–1760 (2000).
Kahn, S.E. The Importance of beta-cell failure in the development and progression of type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 4047–4058 (2001).
Belmonte, S.A. et al. Cholesterol content regulates acrosomal exocytosis by enhancing Rab3A plasma membrane association. Dev. Biol. 285, 393–408 (2005).
Chintagari, N.R. et al. Effect of cholesterol depletion on exocytosis of alveolar type II cells. Am. J. Respir. Cell Mol. Biol. 34, 677–687 (2006).
Chamberlain, L.H., Burgoyne, R.D. & Gould, G.W. SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc. Natl. Acad. Sci. USA 98, 5619–5624 (2001).
Cavaghan, M.K., Ehrmann, D.A., Byrne, M.M. & Polonsky, K.S. Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. J. Clin. Invest. 100, 530–537 (1997).
Higa, M. et al. Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc. Natl. Acad. Sci. USA 96, 11513–11518 (1999).
Shimabukuro, M., Zhou, Y.T., Lee, Y. & Unger, R.H. Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats. J. Biol. Chem. 273, 3547–3550 (1998).
Chawla, A. et al. A PPAR gamma-LXR-Abca1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell 7, 161–171 (2001).
Ruan, X.Z. et al. PPAR agonists protect mesangial cells from interleukin 1{beta}-induced intracellular lipid accumulation by activating the Abca1 cholesterol efflux pathway. J. Am. Soc. Nephrol. 14, 593–600 (2003).
Gerin, I. et al. LXRbeta is required for adipocyte growth, glucose homeostasis, and beta cell function. J. Biol. Chem. 280, 23024–23031 (2005).
Plesner, A., Liston, P., Tan, R., Korneluk, R.G. & Verchere, C.B. The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes 54, 2533–2540 (2005).
Johnson, J.D. et al. Increased islet apoptosis in Pdx1+/− mice. J. Clin. Invest. 111, 1147–1160 (2003).
Rudel, L.L., Kelley, K., Sawyer, J.K., Shah, R. & Wilson, M.D. Dietary monounsaturated fatty acids promote aortic atherosclerosis in LDL receptor-null, human ApoB100-overexpressing transgenic mice. Arterioscler. Thromb. Vasc. Biol. 18, 1818–1827 (1998).
Carr, T.P., Andresen, C.J. & Rudel, L.L. Enzymatic determination of triglyceride, free cholesterol, and total cholesterol in tissue lipid extracts. Clin. Biochem. 26, 39–42 (1993).
Wellington, C.L. et al. Abca1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab. Invest. 82, 273–283 (2002).
Heaps, C.L., Tharp, D.L. & Bowles, D.K. Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles. Am. J. Physiol. Heart Circ. Physiol. 288, H568–H576 (2005).
Acknowledgements
Special thanks to G. Soukhatcheva for performing islet isolations, to A.K. Gebre for technical assistance with islet lipid assays and to A. Plesner for helpful discussions. We thank O. Francone (Pfizer Global Research) for providing the Abca1 global knockout mice. This work was supported by grants from the Canadian Institutes of Health Research (CIHR; to C.B.V. and M.R.H.), the US National Institutes of Health (grant HL 49373 to J.S.P. and B.J.M) and the Juvenile Diabetes Research Foundation (to B.J.M.). L.R.B. is supported by a CIHR studentship and is a doctoral trainee at the Michael Smith Foundation for Health Research (MSFHR). J.K.K. is supported by a Child and Family Research Institute fellowship. Z.V. is supported by the Canadian Diabetes Association (CDA) and MSFHR. C.B.V. is a MSFHR Senior Scholar. J.D.J. is a CIHR, MSFHR and CDA Scholar. M.R.H. holds a Canada Research Chair in Human Genetics and is a University of British Columbia Killam Professor.
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L.R.B. and J.K.K. conducted the in vitro and in vivo experiments and contributed to manuscript writing. T.D.P. and A.Q.R. assisted in conducting experiments. J.M.T. performed measurements of islet cholesterol. Z.V. performed filipin staining. J.D.J. performed islet perifusion studies. B.J.M., B.R. and J.S.P. made conceptual contributions and provided crucial reagents. M.R.H. and C.B.V. supervised the studies and contributed to manuscript writing.
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Supplementary information
Supplementary Fig. 1
Cre-mediated recombination of islet Abca1. (PDF 27 kb)
Supplementary Fig. 2
Western blot of Abca1 expression in hypothalamus of Abca1+/+ and Abca1−P/−P mice. (PDF 86 kb)
Supplementary Fig. 3
β-cell mass in mice lacking β-cell Abca1. (PDF 63 kb)
Supplementary Fig. 4
Plasma total cholesterol levels in Abca1+/+ and Abca1−P/−P mice receiving a chow diet, and following high-fat or high-fat+rosiglitazone feeding. (PDF 20 kb)
Supplementary Table 1
Plasma metabolic parameters in Abca1+/+ and Abca1−P/−P mice. (PDF 10 kb)
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Brunham, L., Kruit, J., Pape, T. et al. β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 13, 340–347 (2007). https://doi.org/10.1038/nm1546
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DOI: https://doi.org/10.1038/nm1546
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