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Non-Alcoholic Fatty Liver Disease and the Metabolic Syndrome

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Book cover Metabolic Basis of Obesity

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a constellation of diseases ranging from benign liver steatosis to fibrosing nonalcoholic steatohepatitis (NASH). Its incidence is on the rise in parallel to obesity. Its clinico-pathogenesis is associated with metabolic syndrome. Accumulation of fat in liver constitutes its mechanistic basis. With liver steatosis being mechanistically linked to insulin action, it is natural to associate NAFLD with insulin resistance. However, this notion has not been universally held, largely because of the limited availability of animal models that best replicate the human disease. This review will emphasize novel mechanisms linking NAFLD pathogenesis to the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), a protein that is implicated in the regulation of insulin and lipid metabolism in liver.

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References

  1. Marrero, J. A., Fontana, R. J., Su, G. L., Conjeevaram, H. S., Emick, D. M., & Lok, A. S. (2002). NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology, 36(6), 1349–1354.

    PubMed  Google Scholar 

  2. Bullock, R. E., Zaitoun, A. M., Aithal, G. P., Ryder, S. D., Beckingham, I. J., & Lobo, D. N. (2004). Association of non-alcoholic steatohepatitis without significant fibrosis with ­hepatocellular carcinoma. Journal of Hepatology, 41(4), 685–686.

    Article  PubMed  Google Scholar 

  3. Erickson, S. K. (2009). Nonalcoholic fatty liver disease. Journal of Lipid Research, 50(Suppl), S412–S416.

    Article  PubMed  Google Scholar 

  4. Lazo, M., & Clark, J. M. (2008). The epidemiology of nonalcoholic fatty liver disease: A global perspective. Seminars in Liver Disease, 28(4), 339–350.

    Article  PubMed  Google Scholar 

  5. Ong, J. P., & Younossi, Z. M. (2007). Epidemiology and natural history of NAFLD and NASH. Clinics in Liver Disease, 11, 1–16.

    Article  PubMed  Google Scholar 

  6. Hui, J. M., Kench, J. G., Chitturi, S., et al. (2003). Long-term outcomes of cirrhosis in ­nonalcoholic steatohepatitis compared with hepatitis C. Hepatology, 38, 420–427.

    Article  PubMed  Google Scholar 

  7. Clark, J. M. (2006). The epidemiology of nonalcoholic fatty liver disease in adults. Journal of Clinical Gastroenterology, 40(3 Suppl 1), S5–S10.

    PubMed  Google Scholar 

  8. Ludwig, J., Viggiano, T. R., McGill, D. B., & Oh, B. J. (1980). Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic Proceedings. Mayo Clinic, 55, 434–438.

    CAS  PubMed  Google Scholar 

  9. Day, C. P., & James, O. F. (1998). Steatohepatitis: A tale of two “hits”? Gastroenterology, 114, 842–845.

    Article  CAS  PubMed  Google Scholar 

  10. Poy, M. N., Yang, Y., Rezaei, K., et al. (2002). CEACAM1 regulates insulin clearance in liver. Nature Genetics, 30(3), 270–276.

    Article  PubMed  Google Scholar 

  11. DeAngelis, A. M., Heinrich, G., Dai, T., et al. (2008). Carcinoembryonic antigen-related cell adhesion molecule 1: A link between insulin and lipid metabolism. Diabetes, 57(9), 2296–2303.

    Article  CAS  PubMed  Google Scholar 

  12. Najjar, S. M., Yang, Y., Fernstrom, M. A., et al. (2005). Insulin acutely decreases hepatic fatty acid synthase activity. Cell Metabolism, 2, 43–53.

    Article  CAS  PubMed  Google Scholar 

  13. Gray-Owen, S. D., & Blumberg, R. S. (2006). CEACAM1: Contact-dependent control of immunity. Nature Reviews. Immunology, 6, 433–446.

    Article  CAS  PubMed  Google Scholar 

  14. Marra, F., Gastaldelli, A., Svegliati Baroni, G., Tell, G., & Tiribelli, C. (2008). Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends in Molecular Medicine, 14, 72–81.

    Article  CAS  PubMed  Google Scholar 

  15. Farrell, G. C. (2009). The liver and the waistline: Fifty years of growth. Journal of Gastroenterology and Hepatology, 24(Suppl 3), S105–S118.

    Article  PubMed  Google Scholar 

  16. Choi, S. S., & Diehl, A. M. (2008). Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Current Opinion in Lipidology, 19(3), 295–300.

    Article  CAS  PubMed  Google Scholar 

  17. Ginsberg, H. N. (2006). Is the slippery slope from steatosis to steatohepatitis paved with ­triglyceride or cholesterol? Cell Metabolism, 4, 179–181.

    Article  CAS  PubMed  Google Scholar 

  18. Haeusler, R. A., & Accili, D. (2008). The double life of Irs. Cell Metabolism, 8, 7–9.

    Article  CAS  PubMed  Google Scholar 

  19. Brown, M. S., & Goldstein, J. L. (2008). Selective versus total insulin resistance: A ­pathogenic paradox. Cell Metabolism, 7, 95–96.

    Article  CAS  PubMed  Google Scholar 

  20. Polonsky, K. S., Given, B. D., Hirsch, L., et al. (1988). Quantitative study of insulin secretion and clearance in normal and obese subjects. Journal of Clinical Investigation, 81, 435–441.

    Article  CAS  PubMed  Google Scholar 

  21. Escobar, O., Mizuma, H., Sothern, M. S., et al. (1999). Hepatic insulin clearance increases after weight loss in obese children and adolescents. American Journal of the Medical Sciences, 317, 282–286.

    Article  CAS  PubMed  Google Scholar 

  22. Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002). SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation, 109, 1125–1131.

    CAS  PubMed  Google Scholar 

  23. Accili, D., Perrotti, N., Rees, J. R., & Taylor, S. I. (1986). Tissue distribution and subcellular localization of an endogenous substrate (pp120) for the insulin receptor-associated tyrosine kinase. Endocrinology, 119, 1274–1280.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Dubois, M. J., Bergeron, S., Kim, H. J., et al. (2006). The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nature Medicine, 12, 549–556.

    Article  CAS  PubMed  Google Scholar 

  26. Park, S. Y., Cho, Y. R., Kim, H. J., et al. (2006). Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1. American Journal of Physiology. Endocrinology and Metabolism, 291, E517–E524.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Biddinger, S. B., Hernandez-Ono, A., Rask-Madsen, C., et al. (2008). Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metabolism, 7, 125–134.

    Article  CAS  PubMed  Google Scholar 

  29. Cantley, L. C. (2002). The phosphoinositide 3-kinase pathway. Science, 296, 1655–1657. Review.

    Article  CAS  PubMed  Google Scholar 

  30. Ward, G. M., Walters, J. M., Aitken, P. M., Best, J. D., & Alford, F. P. (1990). Effects of prolonged pulsatile hyperinsulinemia in humans. Enhancement of insulin sensitivity. Diabetes, 39(4), 501–507.

    Article  CAS  PubMed  Google Scholar 

  31. Lee, S. J., Heinrich, G., Fedorova, L., et al. (2008). Development of non-alcoholic ­steatohepatitis in insulin resistant L-SACC1 mice. Gastroenterology, 135, 2084–2095.

    Article  CAS  PubMed  Google Scholar 

  32. Lee, S. J., Heinrich, G., Fedorova, L., et al. (2008). Development of nonalcoholic ­steatohepatitis in insulin-resistant liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule 1 mutant mice. Gastroenterology, 135(6), 2084–2095.

    Article  CAS  PubMed  Google Scholar 

  33. Mari, M., Caballero, F., Colell, A., et al. (2006). Mitochondrial free cholesterol loading ­sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metabolism, 4, 185–198.

    Article  CAS  PubMed  Google Scholar 

  34. Ariz, U., Mato, J. M., Lu, S. C., & Martinez Chantar, M. L. (2010). Nonalcoholic ­steatohepatitis, animal models, and biomarkers: What is new? Methods in Molecular Biology (Clifton, N.J.), 593, 109–136.

    Article  CAS  Google Scholar 

  35. Anstee, Q. M., & Goldin, R. D. (2006). Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. International Journal of Experimental Pathology, 87(1), 1–16.

    Article  CAS  PubMed  Google Scholar 

  36. Green, R. M. (2003). NASH – hepatic metabolism and not simply the metabolic syndrome. Hepatology, 38(1), 14–17.

    Article  CAS  PubMed  Google Scholar 

  37. Otogawa, K., Kinoshita, K., Fujii, H., et al. (2007). Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: Implications for the pathogenesis of human nonalcoholic steatohepatitis. American Journal of Pathology, 170, 967–980.

    Article  CAS  PubMed  Google Scholar 

  38. Kurlawalla-Martinez, C., Stiles, B., Wang, Y., Devaskar, S. U., Kahn, B. B., & Wu, H. (2005). Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Molecular and Cellular Biology, 25, 2498–2510.

    Article  CAS  PubMed  Google Scholar 

  39. Nakayama, H., Otabe, S., Ueno, T., et al. (2007). Transgenic mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue exhibit liver histology similar to ­nonalcoholic steatohepatitis. Metabolism, 56, 470–475.

    Article  CAS  PubMed  Google Scholar 

  40. Bigorgne, A. E., Bouchet-Delbos, L., Naveau, S., et al. (2008). Obesity-induced lymphocyte hyperresponsiveness to chemokines: A new mechanism of fatty liver inflammation in obese mice. Gastroenterology, 134, 1459–1469.

    Article  PubMed  Google Scholar 

  41. Sheth, S. G., Gordon, F. D., & Chopra, S. (1997). Nonalcoholic steatohepatitis. Annals of Internal Medicine, 126, 137–145.

    CAS  PubMed  Google Scholar 

  42. Li, Z., Soloski, M. J., & Diehl, A. M. (2005). Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology, 42, 880–885.

    Article  CAS  PubMed  Google Scholar 

  43. Kremer, M., Hines, I. N., Milton, R. J., & Wheeler, M. D. (2006). Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis. Hepatology, 44, 216–227.

    Article  CAS  PubMed  Google Scholar 

  44. Tiegs, G. (2007). Cellular and cytokine-mediated mechanisms of inflammation and its ­modulation in immune-mediated liver injury. Zeitschrift fur Gastroenterologie, 45, 63–70.

    Article  CAS  PubMed  Google Scholar 

  45. Nagaishi, T., Pao, L., Lin, S. H., et al. (2006). SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity, 25, 769–781.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Health Science Campus, 3000 Arlington Avenue, Mail Stop 1008, Block Health Science Building, CeDER, Toledo, OH, USA, 43614-2598

    Sonia M. Najjar

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  1. Sonia M. Najjar
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Correspondence to Sonia M. Najjar .

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Editors and Affiliations

  1. School of Medicine, Div. Endocrinology, Diabetes, &, University of Pennsylvania, Curie Blvd. 415, Philadelphia, 19104, Pennsylvania, USA

    Rexford S. Ahima

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Najjar, S.M. (2011). Non-Alcoholic Fatty Liver Disease and the Metabolic Syndrome. In: Ahima, R. (eds) Metabolic Basis of Obesity. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1607-5_12

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  • DOI: https://doi.org/10.1007/978-1-4419-1607-5_12

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