The formation of intracellular glyceraldehyde-derived advanced glycation end-products and cytotoxicity
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Nonalcoholic steatohepatitis (NASH) is a feature of metabolic syndrome. Advanced glycation end-products (AGEs) are formed by the Maillard reaction, which contributes to aging and to certain pathological complications of diabetes. A recent study has suggested that glyceraldehyde-derived AGEs (Glycer-AGEs) are elevated in the sera of patients with NASH. Furthermore, immunohistochemistry of Glycer-AGEs showed intense staining in the livers of patients with NASH. The present study aimed to examine the effect of intracellular Glycer-AGEs on hepatocellular carcinoma (Hep3B) cells.
Cell viability was determined by the WST-1 assay. The slot blot and Western blot were used to detect intracellular Glycer-AGEs, and their localization was analyzed by confocal microscopy. Real-time reverse transcription-polymerase chain reaction was used to quantify the mRNA for the acute phase reactant C-reactive protein (CRP).
Glyceraldehyde (GA), which is the precursor of Glycer-AGEs, induced a concentration- and time-dependent increase in cell death, which was associated with an increase in intracellular Glycer-AGEs formation. Aminoguanidine (AG), which prevents AGEs formation, inhibited the formation of intracellular Glycer-AGEs and prevented cell death. Among the intracellular Glycer-AGEs that were formed, heat shock cognate 70 (Hsc70) was identified as a GA-modified protein, and its modification reduced the activity of Hsc70. Furthermore, intracellular Glycer-AGEs increased the CRP mRNA concentration.
These results suggest that intracellular Glycer-AGEs play important roles in promoting inflammation and hepatocellular death.
- Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8.
- Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–31. CrossRef
- Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9. CrossRef
- Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sørensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–5. CrossRef
- Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–50. CrossRef
- Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9. CrossRef
- Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23. CrossRef
- Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5. CrossRef
- Al-Abed Y, Kapurniotu A, Bucala R. Advanced glycation end products: detection and reversal. Methods Enzymol. 1999;309:152–72. CrossRef
- Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med. 2002;251:87–101. CrossRef
- Glomb MA, Monnier VM. Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. J Biol Chem. 1995;270:10017–26. CrossRef
- Thornalley PJ, Langborg A, Minhas HS. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J. 1999;344:109–16. CrossRef
- Takeuchi M, Bucala R, Suzuki T, Ohkubo T, Yamazaki M, Koike T, et al. Neurotoxicity of advanced glycation end-products for cultured cortical neurons. J Neuropathol Exp Neurol. 2000;59:1094–105.
- Yamagishi S, Amano S, Inagaki Y, Okamoto T, Koga K, Sasaki N, et al. Advanced glycation end products-induced apoptosis and overexpression of vascular endothelial growth factor in bovine retinal pericytes. Biochem Biophys Res Commun. 2002;290:973–8. CrossRef
- Yamagishi S, Inagaki Y, Okamoto T, Amano S, Koga K, Takeuchi M, et al. Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. J Biol Chem. 2002;277:20309–15. CrossRef
- Hyogo H, Yamagishi S, Iwamoto K, Arihiro K, Takeuchi M, Sato T, et al. Elevated levels of serum advanced glycation end products in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2007;22:1112–9. CrossRef
- Yoshida T, Yamagishi S, Nakamura K, Matsui T, Imaizumi T, Takeuchi M, et al. Pigment epithelium-derived factor (PEDF) inhibits advanced glycation end product (AGE)-induced C-reactive protein expression in hepatoma cells by suppressing Rac-1 activation. FEBS Lett. 2006;580:2788–96. CrossRef
- Iwamoto K, Kanno K, Hyogo H, Yamagishi S, Takeuchi M, Tazuma S, et al. Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells. J Gastroenterol. 2008;43:298–304. CrossRef
- Takeuchi M, Makita Z, Bucala R, Suzuki T, Koike T, Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo. Mol Med. 2000;6:114–25.
- Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science. 1986;232:1629–32. CrossRef
- Nicholls K, Mandel TE. Advanced glycosylation end-products in experimental murine diabetic nephropathy: effect of islet isografting and of aminoguanidine. Lab Invest. 1989;60:486–91.
- Khalifah RG, Baynes JW, Hudson BG. Amadorins: novel post-Amadori inhibitors of advanced glycation reactions. Biochem Biophys Res Commun. 1999;257:251–8. CrossRef
- Price DL, Rhett PM, Thorpe SR, Baynes JW. Chelating activity of advanced glycation end-product inhibitors. J Biol Chem. 2001;276:48967–72. CrossRef
- Carbone DL, Doorn JA, Kiebler Z, Sampey BP, Petersen DR. Inhibition of Hsp72-mediated protein refolding by 4-hydroxy-2-nonenal. Chem Res Toxicol. 2004;17:1459–67. CrossRef
- Rodríguez-Ariza A, López-Sánchez LM, González R, Corrales FJ, López P, Bernardos A, et al. Altered protein expression and protein nitration pattern during d-galactosamine-induced cell death in human hepatocytes: a proteomic analysis. Liver Int. 2005;25:1259–69. CrossRef
- Daugaard M, Rohde M, Jäättelä M. The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett. 2007;581:3702–10. CrossRef
- Canbakan B, Senturk H, Tahan V, Hatemi H, Balci H, Toptas T, et al. Clinical, biochemical and histological correlations in a group of non-drinker subjects with non-alcoholic fatty liver disease. Acta Gastroenterol Belg. 2007;70:277–84.
- Bell DS, Allbright E. The multifaceted associations of hepatobiliary disease and diabetes. Endocr Pract. 2007;13:300–12.
- Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and FAS expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–43. CrossRef
- Ribeiro PS, Cortez-Pinto H, Solá S, Castro RE, Ramalho RM, Baptista A, et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am J Gastroenterol. 2004;99:1708–17. CrossRef
- Takeuchi M, Yamagishi S. Alternative routes for the formation of glyceraldehyde-derived AGEs (TAGE) in vivo. Med Hypotheses. 2004;63:453–5. CrossRef
- Taniguchi S, Okinaka M, Tanigawa K, Miwa I. Difference in mechanism between glyceraldehyde- and glucose-induced insulin secretion from isolated rat pancreatic islets. J Biochem. 2000;127:289–95.
- Takahashi H, Tran PO, LeRoy E, Harmon JS, Tanaka Y, Robertson RP. d-Glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways. J Biol Chem. 2004;279:37316–23. CrossRef
- Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y, et al. Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Biochem Biophys Res Commun. 2003;300:216–22. CrossRef
- Hamelin M, Mary J, Vostry M, Friguet B, Bakala H. Glycation damage targets glutamate dehydrogenase in the rat liver mitochondrial matrix during aging. FEBS J. 2007;274:5949–61. CrossRef
- Kumar PA, Kumar MS, Reddy GB. Effect of glycation on alpha-crystallin structure and chaperone-like function. Biochem J. 2007;408:251–8. CrossRef
- Schalkwijk CG, van Bezu J, van der Schors RC, Uchida K, Stehouwer CD, van Hinsbergh VW. Heat-shock protein 27 is a major methylglyoxal-modified protein in endothelial cells. FEBS Lett. 2006;580:1565–70. CrossRef
- Gomes RA, Miranda HV, Silva MS, Graça G, Coelho AV, Ferreira AE, et al. Yeast protein glycation in vivo by methylglyoxal. Molecular modification of glycolytic enzymes and heat shock proteins. FEBS J. 2006;273:5273–87. CrossRef
- Yoneda M, Mawatari H, Fujita K, Iida H, Yonemitsu K, Kato S, et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol. 2007;42:573–82. CrossRef
- Targher G, Bertolini L, Rodella S, Lippi G, Franchini M, Zoppini G, et al. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity. 2008;16:1394–9. CrossRef
- The formation of intracellular glyceraldehyde-derived advanced glycation end-products and cytotoxicity
Journal of Gastroenterology
Volume 45, Issue 6 , pp 646-655
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