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CEACAM1 regulates insulin clearance in liver

Nature Genetics volume 30, pages 270–276 (2002)Cite this article

Abstract

We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.

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Figure 1: Generation of L-SACC1 mice.
Figure 2: Specific alteration of hepatic CEACAM1 phosphorylation in L-SACC1 mice.
Figure 3: Growth curves of age-matched wildtype and L-SACC1 mice.
Figure 4: Hyperinsulinemia in L-SACC1 mice is due to impaired insulin clearance.
Figure 5: Secondary insulin resistance in L-SACC1 mice.
Figure 6: Normal pancreatic β-cell function in L-SACC1homo mice.

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References

  1. Backer, J.M. et al. Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. J. Biol. Chem. 267, 1367–1374 (1992).

    CAS  PubMed  Google Scholar 

  2. Baumann, C.A. et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407, 202–207 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Mathews, S.T. et al. Alpha2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol. Cell. Endocrinol. 164, 87–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Maddux, B.A. & Goldfine, I.D. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor α-subunit. Diabetes 49, 13–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Najjar, S.M. et al. Insulin-stimulated phosphorylation of recombinant pp120/HA4, an endogenous substrate of the insulin receptor tyrosine kinase. Biochemistry 34, 9341–9349 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Cheung, P.H. et al. Cell-CAM105 isoforms with different adhesion functions are coexpressed in adult rat tissues and during liver development. J. Biol. Chem. 268, 6139–6146 (1993).

    CAS  PubMed  Google Scholar 

  7. Hsieh, J.-T. et al. Tumor suppressive role of an androgen-regulated epithelial cell adhesion molecule (C-CAM) in prostate carcinoma cell revealed by sense and antisense approaches. Cancer Res. 55, 190–197 (1995).

    CAS  PubMed  Google Scholar 

  8. Luo, W., Wood, C.G., Earley, K., Hung, M.C. & Lin, S.H. Suppression of tumorigenicity of breast cancer cells by an epithelial cell adhesion molecule (C-CAM1): the adhesion and growth suppression are mediated by different domains. Oncogene 14, 1697–1704 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Rosenberg, M. et al. The expression of mouse biliary glycoprotein, a carcinoembryonic antigen-related gene, is down-regulated in malignant mouse tissues. Cancer Res. 53, 4938–4945 (1993).

    CAS  PubMed  Google Scholar 

  10. Neumaier, M., Paululat, S., Chan, A., Matthaes, P. & Wagener, C. Biliary glycoprotein, a potential human cell adhesion molecule, is down-regulated in colorectal carcinomas. Proc. Natl Acad. Sci. USA 90, 10744–10748 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li Calzi, S., Choice, C.V. & Najjar, S.M. Differential effect of pp120 on insulin endocytosis by two variant insulin receptor isoforms. Am. J. Physiol. 273, E801–808 (1997).

    CAS  PubMed  Google Scholar 

  12. Formisano, P. et al. Receptor-mediated internalization of insulin. Potential role of pp120/HA4, a substrate of the insulin receptor kinase. J. Biol. Chem. 270, 24073–24077 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Soni, P., Lakkis, M., Poy, M.N., Fernstrom, M.A. & Najjar, S.M. The differential effects of pp120 (Ceacam 1) on the mitogenic action of insulin and insulin-like growth factor 1 are regulated by the nonconserved tyrosine 1316 in the insulin receptor. Mol. Cell. Biol. 20, 3896–3905 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Choice, C.V., Howard, M.J., Poy, M.N., Hankin, M.H. & Najjar, S.M. Insulin stimulates pp120 endocytosis in cells co-expressing insulin receptors. J. Biol. Chem. 273, 22194–22200 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Duckworth, W.C., Bennett, R.G. & Hamel, F.G. Insulin degradation: progress and potential. Endocr. Rev. 19, 608–624 (1998).

    CAS  PubMed  Google Scholar 

  16. Han, E. et al. Differences in tissue-specific and embryonic expression of mouse Ceacam1 and Ceacam2 genes. Biochem. J. 355, 417–423 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, X., Iqbal, N. & Boden, G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J. Clin. Invest. 103, 365–372 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Michael, M.D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Najjar, S.M., Choice, C.V., Soni, P., Whitman, C.M. & Poy, M.N. Effect of pp120 on receptor-mediated insulin endocytosis is regulated by the juxtamembrane domain of the insulin receptor. J. Biol. Chem. 273, 12923–12928 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Svedberg, J., Stromblad, G., Wirth, A., Smith, U. & Bjorntorp, P. Fatty acids in the portal vein of the rat regulate hepatic insulin clearance. J. Clin. Invest. 88, 2054–2058 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Escobar, O. et al. Hepatic insulin clearance increases after weight loss in obese children and adolescents. Am. J. Med. Sci. 317, 282–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Bosello, O. et al. Modifications of abdominal fat and hepatic insulin clearance during severe caloric restriction. Ann. Nutr. Metab. 34, 359–365 (1990).

    Article  CAS  PubMed  Google Scholar 

  23. Peiris, A.N., Mueller, R.A., Smith, G.A., Struve, M.F. & Kissebah, A.H. Splanchnic insulin metabolism in obesity. Influence of body fat distribution. J. Clin. Invest. 78, 1648–1657 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Svedberg, J., Bjorntorp, P., Smith, U. & Lonnroth, P. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 39, 570–574 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Hennes, M.M., Shrago, E. & Kissebah, A.H. Receptor and postreceptor effects of free fatty acids (FFA) on hepatocyte insulin dynamics. Int. J. Obes. 14, 831–841 (1990).

    CAS  PubMed  Google Scholar 

  26. Ferrannini, E., Barrett, E.J., Bevilacqua, S. & DeFronzo, R.A. Effect of fatty acids on glucose production and utilization in man. J. Clin. Invest. 72, 1737–1747 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kissebah, A.H., Alfarsi, S., Adams, P.W. & Wynn, V. Role of insulin resistance in adipose tissue and liver in the pathogenesis of endogenous hypertriglyceridaemia in man. Diabetologia 12, 563–571 (1976).

    Article  CAS  PubMed  Google Scholar 

  28. Rooney, D.P. & Robertson, R.P. Hepatic insulin resistance after pancreas transplantation in type I diabetes. Diabetes 45, 134–138 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Diem, P., Abid, M., Redmon, J.B., Sutherland, D.E. & Robertson, R.P. Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes 39, 534–540 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Bergman, R.N. & Ader, M. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol. Metab. 11, 351–356 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Bergman, R.N. Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein? Diabetologia 43, 946–952 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Reaven, G.M. & Chen, Y.D. Role of insulin in regulation of lipoprotein metabolism in diabetes. Diabetes Metab. Rev. 4, 639–652 (1988).

    Article  CAS  PubMed  Google Scholar 

  33. Randle, P.J., Garland, P.B., Newsholme, E.A. & Hales, C.N. The glucose fatty acid cycle in obesity and maturity onset diabetes mellitus. Ann. NY Acad. Sci. 131, 324–333 (1965).

    Article  CAS  PubMed  Google Scholar 

  34. Randle, P.J., Priestman, D.A., Mistry, S. & Halsall, A. Mechanisms modifying glucose oxidation in diabetes mellitus. Diabetologia 37, S155–161 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Nestel, P.J., Ishikawa, T. & Goldrick, R.B. Diminished plasma free fatty acid clearance in obese subjects. Metabolism 27, 589–597 (1978).

    Article  CAS  PubMed  Google Scholar 

  36. Koopmans, S.J., Kushwaha, R.S. & DeFronzo, R.A. Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis but does not cause dyslipidemia in conscious normal rats. Metabolism 48, 330–337 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Kido, Y. et al. Tissue-specific insulin resistance in mice with combined mutations in the insulin receptor, IRS-1, and IRS-2. J. Clin. Invest. 105, 199–205 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim, J.K. et al. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J. Clin. Invest. 105, 1791–1797 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Walsh, A., Ito, Y. & Breslow, J.L. High levels of human apolipoprotein A-I in transgenic mice result in increased plasma levels of small high density lipoprotein (HDL) particles comparable to human HDL. J. Biol. Chem. 264, 6488–6494 (1989).

    CAS  PubMed  Google Scholar 

  40. Bisaha, J.G., Simon, T.C., Gordon, J.I. & Breslow, J.L. Characterization of an enhancer element in the human apolipoprotein C-III gene that regulates human apolipoprotein A-I gene expression in the intestinal epithelium. J. Biol. Chem. 270, 19979–19988 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Najjar, S.M. et al. pp120/ecto-ATPase, an endogenous substrate of the insulin receptor tyrosine kinase, is expressed as two variably spliced isoforms. J. Biol. Chem. 268, 1201–1206 (1993).

    CAS  PubMed  Google Scholar 

  42. Najjar, S.M. et al. Cloning and characterization of a functional promoter of the rat pp120 gene, encoding a substrate of the insulin receptor tyrosine kinase. J. Biol. Chem. 271, 8809–8817 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Folch, J., Lees, M. & Sloane-Stanley, G.H. A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226, 497–509 (1957).

    CAS  PubMed  Google Scholar 

  44. Mondon, C.E., Olefsky, J.M., Dolkas, C.B. & Reaven, G.M. Removal of insulin by perfused rat liver: effect of concentration. Metabolism 24, 153–160 (1975).

    Article  CAS  PubMed  Google Scholar 

  45. Cinti, S., Eberbach, S., Castellucci, M. & Accili, D. Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphological and ultrastructural analysis. Diabetologia 41, 171–177 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Ruch, R.J. & Klaunig, J.E. Kinetics of phenobarbital inhibition of intercellular communication in mouse hepatocytes. Cancer Res. 48, 2519–2523 (1988).

    CAS  PubMed  Google Scholar 

  47. Lee, A.D., Gulve, E.A., Chen, M., Schluter, J. & Holloszy, J.O. Effects of Ca2+ ionophore ionomycin on insulin-stimulated and basal glucose transport in muscle. Am. J. Physiol. 268, R997–1002 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Lee, C.H. et al. Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. Proc. Natl Acad. Sci. USA 90, 11713–11717 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Accili, S.F. Previs and G.I. Shulman for critical reading of the manuscript and for helpful scientific discussions, and E.M. Rubin and N. Beauchemin for providing the apolipoprotein A-1 promoter cDNA and anti-mouse BGP antibodies, respectively. We thank S. Robson, E. Tietz and S. Lilly for assistance in immunohistochemistry and microscopy, and T. Dai and R. Ruch for assistance in primary hepatocytes. We also thank the Ohio University Edison Biotechnology Institute Collaborative Transgenics, Athens, Ohio for performing DNA microinjections as part of their service grant support (to S.M.N.). This work was chiefly supported by two grants from the National Institutes of Health–National Institute of Diabetes & Digestive & Kidney Diseases (to S.M.N.), and partially by Sigma-Tau Research (to S.M.N.) and the Department of Veterans Affairs (to S.K.E.). M.N.P. was partially supported by the Institutional Pre-doctoral National Research Service Award fellowship from the National Institutes of Health.

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Authors and Affiliations

  1. Departments of Pharmacology and Therapeutics, 3035 Arlington Avenue, HSci Building Room 270, Toledo, 43614, Ohio, USA

    Matthew N. Poy, Yan Yang, Khadijeh Rezaei, Mats A. Fernström & Sonia M. Najjar

  2. Physical Therapy, Medical College of Ohio, 3035 Arlington Avenue, HSci Building Room 270, Toledo, 43614, Ohio, USA

    Abraham D. Lee

  3. Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan

    Yoshiaki Kido

  4. Department of Medicine, San Francisco and the Veterans Affairs Medical Center, University of California, San Francisco, California, USA

    Sandra K. Erickson

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Poy, M., Yang, Y., Rezaei, K. et al. CEACAM1 regulates insulin clearance in liver. Nat Genet 30, 270–276 (2002). https://doi.org/10.1038/ng840

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