Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation

Nature Medicine volume 7, pages 840–846 (2001)Cite this article

Abstract

Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increased in endarterectomy lesions from patients with a history of hyperglycemia. Macrophages that were differentiated from human peripheral blood monocytes in the presence of high glucose concentrations showed increased expression of cell-surface CD36 secondary to an increase in translational efficiency of CD36 mRNA. We obtained similar data from primary cells isolated from human vascular lesions, and we found that glucose sensitivity is a function of ribosomal reinitiation following translation of an upstream open reading frame (uORF). Increased translation of macrophage CD36 transcript under high glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CD36 expression by tissue macrophages in vascular lesions.
Figure 2: Immunologic and functional expression of CD36.
Figure 3: RNA analysis.
Figure 4: Secondary structure of CD36 5′-UTR.
Figure 5: Role of CD36 5′-UTR in glucose-mediated increase in translation.
Figure 6: Mechanism of glucose-mediated increase in translation.

Similar content being viewed by others

References

  1. Semenkovich, C.F. & Heinecke, J.W. Perspectives in diabetes: the mystery of diabetes and atherosclerosis. Diabetes 46, 327–334 (1997).

    Article  CAS  Google Scholar 

  2. Schmidt, A. et al. RAGE: A novel cellular receptor for advanced glycation end products. Diabetes 45, 77–80 (1996).

    Article  Google Scholar 

  3. Vlassara, H. Recent progress in advanced glycation end products and diabetic complications. Diabetes 46, 19–24 (1997).

    Article  Google Scholar 

  4. Berliner, J.A. Atherosclerosis: Basic mechanisms. Circulation 91, 2488–2496 (1995).

    Article  CAS  Google Scholar 

  5. Boring, L., Gosling, J., Cleary, M. & Charo, I.F. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998).

    Article  CAS  Google Scholar 

  6. Witzium, J.L. & Steinberg, D. Role of oxidized low density lipoprotein in atherogenesis. J. Clin. Invest. 88, 1785–1792 (1991).

    Article  Google Scholar 

  7. Nagy, L., Tontonoz, P., Alvarez, J., Chen, H. & Evans, R. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 93, 229–240 (1998).

    Article  CAS  Google Scholar 

  8. Tontonoz, P., Nagy, L., Alvarez, J., Thomazy, V. & Evans, R. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93, 241–252 (1998).

    Article  CAS  Google Scholar 

  9. Endemann, G. et al. CD36 is a receptor for oxidized low density lipoprotein. J. Biol. Chem. 268, 11811–11816 (1993).

    CAS  Google Scholar 

  10. Huh, H., Pearce, S.F., Yesner, L.M., Schindler, J.L. & Silverstein, R.L. Regulated expression of CD36 during monocyte to macrophage differentiation: potential role of CD36 in foam cell formation. Blood 87, 2020–2028 (1996).

    CAS  PubMed  Google Scholar 

  11. Nozaki, S. Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. J. Clin. Invest. 96, 1859–1865 (1995).

    Article  CAS  Google Scholar 

  12. Podrez, E. et al. Macrophage scavenger receptor CD36 is the major recptor for LDL modified by monocyte-generated reactive nitrogen species. J. Clin. Invest. 105, 1095–1108 (2000).

    Article  CAS  Google Scholar 

  13. Febbraio, M. et al. Targeted disruption of the class B scavenger receptor, CD36, protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105, 1049–1056 (2000).

    Article  CAS  Google Scholar 

  14. Spiegelman, A. PPARγ in monocytes: less pain, any gain? Cell 93, 153–155 (1998).

    Article  CAS  Google Scholar 

  15. Greenwalt, D.E., Scheck, S.H. & Rhinehart-Jones, T. Heart CD36 expression is increased in murine models of diabetes and in mice fed a high fat diet. J. Clin. Invest. 96, 1382–1388 (1995).

    Article  CAS  Google Scholar 

  16. McCaffrey, T. et al. Decreased Type II/Type I TGF-β1 receptor ratio in cells derived from human atherosclerotic lesions: Conversion from an antiproliferative to profibrotic response to TGF-β1. J. Clin. Invest. 96, 2667–2675 (1995).

    Article  CAS  Google Scholar 

  17. Kolm-Litty, V., Sauer, U., Nerlich, A., Lehmann, R. & Scheicher, E.D. High glucose-induced transforming growth factor b-1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J. Clin. Invest. 101, 160–169 (1998).

    Article  CAS  Google Scholar 

  18. Ashe, M., DeLong, S. & Sachs, A. Glucose depletion rapidly inhibits translation initiation in yeast. Mol. Biol. Cell 11, 833–848 (2000).

    Article  CAS  Google Scholar 

  19. Skelly, R.H., Schuppin, G.T., Ishihara, H., Oka, Y. & Rhodes, C.J. Glucose-regulated translational control of proinsulin biosynthesis with that of the proinsulin endopeptidases PC2 and PC3 in the insulin-producing MIN6 cell line. Diabetes 45, 37–43 (1996).

    Article  CAS  Google Scholar 

  20. Iynedjian, P.B. et al. Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans. Proc. Natl. Acad. Sci. USA 86, 7838–7842 (1989).

    Article  CAS  Google Scholar 

  21. Semenkovich, C.F., Coleman, T. & Fiedorek, F.T.J. Human fatty acid synthase mRNA: tissue distribution, genetic mapping, and kinetics of decay after glucose deprivation. J. Lipid Res. 36, 1507–1520 (1995).

    CAS  PubMed  Google Scholar 

  22. Guest, P.C., Bailyes, E.M., Rutherford, N.G. & Hutton, J.C. Insulin secretory granule biogenesis. Co-ordinate regulation of the biosynthesis of the majority of constituent proteins. Biochem J. 274, 73–78 (1991).

    Article  CAS  Google Scholar 

  23. Hinnebusch, A.G. in Translational Control (eds. Hershey, J.W.B., Mathews, M.B. & Sonenberg, N.) 199–244 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1996).

    Google Scholar 

  24. Gilligan, M. et al. Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. J. Biol. Chem. 271, 2121–2125 (1996).

    Article  CAS  Google Scholar 

  25. Morris, D. & Geballe, A. Upstream open reading frames as regulators of mRNA translation. Mol. Cell. Biol. 20, 8635–8642 (2000).

    Article  CAS  Google Scholar 

  26. Abastado, J., Miller, P., Jackson, B. & Hinnebusch, A. Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control. Mol. Cell. Biol. 11, 486–496 (1991).

    Article  CAS  Google Scholar 

  27. Laakso, M. & Muusisto, J. Epidemiological evidence for the association of hyperglycemia and atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Ann. Med. 28, 415–418 (1996).

    Article  CAS  Google Scholar 

  28. Schmidt, A., Yan, S., Wautier, J. & Stern, D. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ. Res. 84, 489–497 (1999).

    Article  CAS  Google Scholar 

  29. Ohgami, N. et al. CD36, a member of the class B scavenger receptor family, as a receptor for advanced glycation endproducts. J. Biol. Chem. 276, 3195–3202 (2001).

    Article  CAS  Google Scholar 

  30. Hunt, J. V., Bottoms, M. A., Clare, K., Skamarauskas, I. T. & Mitchinson, M. Glucose oxidation and low-density lipoprotein-induced macrophage ceroid accumulation: possible implications for diabetic atherosclerosis. Biochem. J. 300, 243–249 (1994).

    Article  CAS  Google Scholar 

  31. Aitman, T. et al. Identification of CD36 (FAT) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genet 21, 76–83 (1999).

    Article  CAS  Google Scholar 

  32. Febbraio, M. et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem. 274, 19055–19062 (1999).

    Article  CAS  Google Scholar 

  33. Barak, Y. et al. PPARγ is required for placental, cardiac and adipose tissue development. Mol. Cell 4, 585–595 (1999).

    Article  CAS  Google Scholar 

  34. Barroso, I. et al. Dominant negative mutations in human PPARγ associated with sever insulin resistance, diabetes mellitus and hypertension. Nature 402, 880–883 (1999).

    Article  CAS  Google Scholar 

  35. El-Jack, A., Hamm, J., Pilch, P. & Farmer, S. Reconstitution of insulin-sensitive glucose transport in fibroblasts requires expression of both PPARγ and C/EBPalpha. J. Biol. Chem. 274, 7946–7951 (1999).

    Article  CAS  Google Scholar 

  36. Le, S.-Y. & Maizel, J.V.J. A common RNA structural motif involved in the internal initiation of translation of cellular mRNAs. Nucleic Acids Res. 25, 362–369 (1997).

    Article  CAS  Google Scholar 

  37. Koromilas, A. E., Lasaris-Karatzas, A. & Sonenberg, N. mRNAs containing extensive secondary structure in their 5′ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J. 4153–4158 (1992).

  38. Kozak, M. Regulation of translation in eukaryotic systems. Annu. Rev. Cell Biol. 8, 197–225 (1996).

    Article  Google Scholar 

  39. Davuluri, R., Suzuki, Y., Sugano, S. & Zhang, M.Q. CART Classification of HNuman 5′ UTR Sequences. Genome Research 10, 1807–1816 (2000).

    Article  CAS  Google Scholar 

  40. Beaumont, C. et al. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nature Genet. 11, 444–446 (1995).

    Article  CAS  Google Scholar 

  41. Mach, M., White, M.W., Neubauer, M., Degen, J.L. & Morris, D.R. Isolation of a cDNA clone encoding S-adenosylmethionine decarboxylase: expression of the gene in mitogen-activated lymphocytes. J. Biol. Chem. 261, 11697–11703 (1986).

    CAS  PubMed  Google Scholar 

  42. Ho, S.N., Hunt, H.D., Horton, R.M., Pullen, J.K. & Pease, L.R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51–59 (1989).

    Article  CAS  Google Scholar 

  43. Zuker, M., Mathews, D. & Turner, D. in RNA Biochemistry and Biotechnology (ed. Clark, J.B.) 11–43 (Kluwer Academic, Dordrecht, the Netherlands, 1999).

    Book  Google Scholar 

  44. Mathews, D., Sabina, J., Zuker, M. & Turner, D. Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. J. Mol. Biol. 288, 911–940 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Han for the gift of labeled Ox-LDL; F. Pearce for advice on the Ox-LDL studies; A. Cerutti for help with some of the flow cytometry; and M.J.R. Echevarria, D. Falcone and R. Nachman for their critical review of the manuscript. This research was supported by grants from the NIH (DK48698) and American Heart Association (to A.S.A.) and from Universita degli Studi di Parma, Parma, Italy (to A.R.).

Author information

Authors and Affiliations

  1. Weill Medical College of Cornell University, New York, New York, USA

    Erik Griffin, Alessandro Re, Nance Hamel, Chenzong Fu, Harry Bush, Timothy McCaffrey & Adam S. Asch

Authors
  1. Erik Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandro Re
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nance Hamel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chenzong Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Harry Bush
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Timothy McCaffrey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adam S. Asch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adam S. Asch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Griffin, E., Re, A., Hamel, N. et al. A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation. Nat Med 7, 840–846 (2001). https://doi.org/10.1038/89969

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/89969

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing