Abstract
The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat , as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.
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References
Reaven, G.M. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 37, 1595–1607 (1988).
Groop, L.C., Bonadonna, R.C., DelPrato, S., Ratheiser, K. & Zyck, K. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus: evidence for multiple sites of insulin resistance. J. Clin. Invest. 84, 205–213 (1989).
Reaven, G.M., Lithell, H. & Landsberg, L. Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system. N. Engl. J. Med. 334, 374–381 ( 1996).
Aitman, T.J. et al. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 17, 748–754 ( 1997).
Grundy, S.M., Chait, A. & Brunzell, J.D. Meeting summary: familial combined hyperlipidemia workshop. Arteriosclerosis 7, 203– 207 (1987).
Nathan, D.M. Diabetes and the heart. Lancet 350 (suppl. 1), 1–32 (1997).
Iritani, N., Fukuda, E., Nara, Y. & Yamori, Y. Lipid metabolism in spontaneously hypertensive rats (SHR). Atherosclerosis 28, 217–222 (1977).
Reaven, G.M., Chang, H., Hoffman, B.B. & Azhar, S. Resistance to insulin-stimulated glucose uptake in adipocytes from spontaneously hypertensive rats. Diabetes 38, 1155–1160 ( 1989).
Rao, R.H. Insulin resistance in spontaneously hypertensive rats: difference in interpretation based on insulin infusion rate or on plasma insulin in glucose clamp studies. Diabetes 42, 1364–1371 (1993).
Aitman, T.J. et al. Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats. Nature Genet. 16, 197–201 (1997).
Reynisdottir, S., Ellerfeldt, K., Wahrenberg, H., Lithell, H. & Arner, P. Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. J. Clin. Invest. 93, 2590–2599 (1994).
Reynisdottir, S., Eriksson, M., Angelin, B. & Arner, P. Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia. J. Clin. Invest. 95, 2161– 2169 (1995).
Bougneres, P. et al. In vivo resistance of lipolysis to epinephrine. A new feature of childhood onset obesity. J. Clin. Invest. 99, 2568–2573 (1997).
Hilbert, P. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353, 521–529 (1991).
Jacob, H.J. et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67, 213–224 (1991).
Samani, N.J. et al. A gene differentially expressed in the kidney of the sponaneously hypertensive rat cosegregates with increased blood pressure. J. Clin. Invest. 92, 1099–1103 (1993).
Pravenec, M. et al. Mapping of quantitative trait loci for blood pressure and cardiac mass in the rat by genome scanning of recombinant inbred strains. J. Clin. Invest. 96, 1973– 1978 (1995).
Pravenec, M. et al. Mapping genes controlling hematocrit in the spontaneously hypertensive rat. Mamm. Genome 8, 387– 389 (1997).
Bottger, A. et al. Quantitative trait loci influencing cholesterol and phospholipid phenotypes map to chromosomes that contain genes regulating blood pressure in the spontaneously hypertensive rat. J. Clin. Invest. 98, 856–862 (1996).
Kovacs, P. & Kloting, I. Quantitative trait loci on chromosomes 1 and 4 affect lipid phenotypes in the rat. Arch. Biochem. Biophys. 354, 139–143 ( 1998).
Pravenec, M. et al. A genetic linkage map of the rat derived from recombinant inbred strains. Mamm. Genome 7, 117– 127 (1996).
Abumrad, N.A., Harmon, C.M. & Ibrahimi, A. Membrane transport of long-chain fatty acids: Evidence for a facilitated process. J. Lipid Res. (in press).
Tontonoz, P., Nagy, L., Alvarez, J.G.A., Thomszy, V.A. & Evans, R.M. PPAR γ promotes monocyte/macrophage differentiation and uptake of oxidised LDL. Cell 93 , 241–252 (1998).
Spiegelman, B.M. & Flier, J.S. Adipogenesis and obesity: rounding out the big picture. Cell 87, 377–389 (1996).
Savill, J. Apoptosis: phagocytic docking without shocking. Nature 392, 442–443 (1998).
Endemann, G. et al. CD36 is a receptor for oxidised low density lipoprotein. J. Biol. Chem. 268, 11811–11816 (1993).
Nagy, L., Tontonoz, P., Alvarez, J.G.A., Chen, H. & Evans, R.M. Oxidised LDL regulates macrophage gene expression through ligand activation of PPAR γ. Cell 93, 229–240 ( 1998).
Ristow, M., Muller-Wieland, D., Pfeiffer, A., Krone, W. & Kahn, C.R. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N. Engl. J. Med. 339, 953–959 ( 1998).
Randle, P.J., Garland, P.B., Hales, C.N. & Newsholme, E.A. The glucose fatty-acid cycle. Lancet i, 785–789 (1963).
Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859– 2865 (1996).
McGarry, J.D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258, 766–770 ( 1992).
Qu, X. & Donnelly, R. Is insulin resistance in the spontaneously hypertensive rat related to changes in protein kinase C in skeletal muscle? Am. J. Hypertens. 10, 1053– 1057 (1997).
Calvo, D., Gomez-Coronado, D., Suarez, Y., Lasuncion, M.A. & Vega, M.A. Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J. Lipid Res. 39, 777–788 (1998).
Kunz, H.W. & Gill, T.J. III Red blood cell alloantigenic systems in the rat. J. Immunogenet. 5, 365 –382 (1978).
Lifton, R.P. et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nature Genet. 2, 66–74 (1992).
Kashiwagi, H. et al. Molecular basis of CD36 deficiency: Evidence that a 478C-T substitution (Proline90-Serine) in CD36 cDNA accounts for CD36 deficiency. J. Clin. Invest. 95, 1040– 1046 (1995).
Urwijitaroon, Y., Barusrux, S., Romphruk, A. & Puapairoj, C. Frequency of human platelet antigens among blood donors in northeastern Thailand. Transfusion 35, 868–870 (1995).
Curtis, B.R. & Aster, R.H. Incidence of the Naka–negative platelet phenotype in African Americans is similar to that of Asians. Transfusion 36, 331–334 (1996).
Tanaka, T., Sohmiya, K. & Kawamura, K. Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? J. Mol. Cell. Cardiol. 29, 121–127 (1997).
Watanabe, K. et al. Different patterns of 123I-BMIPP myocardial accumulation in patients with type I and II CD36 deficiency. Kaku Igaku 34, 1125–1130 (1997).
Hwang, E.-H. et al. Absent myocardial iodine-123-BMIPP uptake and platelet/monocyte CD36 deficiency. J. Nucl. Med. 39, 1681– 1684 (1998).
Goldmuntz, E.A. et al. Genetic map of 16 polymorphic markers forming three linkage groups assigned to rat chromosome 4. Mamm. Genome 6 , 459–463 (1995).
Schena, M. et al. Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. Proc. Natl Acad. Sci. USA 93, 10614–10619 (1996).
Cox, D.R., Burmeister, M., Price, E.R., Kim, S. & Myers, R.M. Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes. Science 250, 245–250 (1990).
Lange, K., Boehnke, M., Cox, D.R. & Lunetta, K.L. Statistical methods for polyploid radiation hybrid mapping. Genome Res. 5, 136–150 (1995).
Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156– 159 (1987).
Ibrahimi, A. et al. Expression of the CD36 homolog (FAT) in fibroblast cells: effects on fatty acid transport. Proc. Natl Acad. Sci. USA 93, 2646–2651 (1996).
Levak-Frank, S. et al. Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J. Clin. Invest. 96, 976–986 (1995).
Armesilla, A.L. & Vega, M.A. Structural organization of the gene for human CD36 glycoprotein. J. Biol. Chem. 269, 18985–18991 (1994).
Taylor, K.T., Tang, Y., Sobieski, D.A. & Lipsky, R.H. Characterization of two alternatively spliced 5´-untranslated exons of the human CD36 gene in different cell types. Gene 133, 205–212 (1993).
Acknowledgements
This work was carried out under intramural funding from the MRC Clinical Sciences Centre. We acknowledge support from the British Heart Foundation (grant no. PG/95185 and PG/98022) and the European Community Concerted Action on Blood Pressure to T.J.A.; NIH grant RO1 HL56028 to T.W.K.; grant 204/98/K015 from the Grant Agency of the Czech Republic to M.P.; and NIH grant DK33301 and the Sumitomo Chemical Company to N.A.A. M.P. is an International Scholar of the Howard Hughes Medical Institute. J.S. was supported by a Bristol Myers Squibb Award for Cardiovascular Research.
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Aitman, T., Glazier, A., Wallace, C. et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat Genet 21, 76–83 (1999). https://doi.org/10.1038/5013
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DOI: https://doi.org/10.1038/5013
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