FPS-ZM1 Alleviates Circulating Indices of Liver Injury in Diet-Induced Type 2 Diabetic Mice
Abstract
Despite dietary/lifestyle modifications as well as glycemic and lipid control, non-alcoholic fatty liver disease (NAFLD) imposes a considerable risk to the patients by advancing to non-alcoholic steatohepatitis (NASH). The present investigation aims to evaluate the protective potential of FPS-ZM1, a selective inhibitor for advanced glycation end products (RAGE), against circulating indices of liver injury in high fat diet-induced diabetic mice. FPS-ZM1 at 0.5. 1, and 2 mg/kg (orally) was administered for 2 months, starting 4 months after provision of the high-fat diet. Tests for glucose homeostasis, liver injury markers, and hepatic/plasma miR-21 expressions were performed. FPS-ZM1 attenuated diabetes-induced elevations in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLD), and alpha glutathione-S-transferase (α-GST) as well as alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). It also decreased diabetes-associated elevations in serum ferritin and plasma cytokeratin 18 fragments. Additionally, FPS-ZM1 down-regulated elevated expressions of miR-21 in the liver and plasma of diabetic mice. These findings highlight the benefits of FPS-ZM in alleviating liver injury in mice evoked by high-fat diet-induced type 2 diabetes and suggest FPS-ZM1 as a new potential adjunct to the conventional diet/lifestyle modification and glycemic control in diabetics.
1. Ahmad SNS, Nourollahi S, Nakhjavani M, Khojastehfard M, Mostafazadeh M, Hajipour H, et al. Preptin and myostatin independently increase in pre-diabetics and patients of type 2 diabetes mellitus Acta Med Iran 2019;57:160-6.
2. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012;56:943-51.
3. Cobbina E, Akhlaghi F. Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters. Drug Metab Rev 2017;49:197-211.
4. Alkassabany YM, Farghaly AG, El-Ghitany EM. Prevalence, risk factors, and predictors of nonalcoholic fatty liver disease among schoolchildren: a hospital-based study in Alexandria, Egypt. Arab J Gastroenterol 2014;15:76-81.
5. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013;10:627-6.
6. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-307.
7. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85.
8. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-90.
9. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016;65:369-76.
10. Dajani AI, Abu Hammour AM, Zakaria MA, Al Jaberi MR, Nounou MA, Semrin AI. Essential phospholipids as a supportive adjunct to the management of patients with primary NAFLD and NAFLD associated with type 2 diabetes mellitus or hyperlipidaemia. Hepatol Int 2013;7:748-54.
11. Mohamed WS, Mostafa AM, Mohamed JM, Serwah AH. Effects of fenugreek, Nigella, and termis seeds in nonalcoholic fatty liver in obese diabetic albino rats. Arab J Gastroenterol 2015;16:1-9.
12. Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Ueda T, Tsutsumi M, et al. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies. World J Hepatol 2014;6:880-93.
13. Leung C, Herath BC, Jia Z, Andrikopoulos S, Brown BE, Davies MJ, et al. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease. World J Gastroenterol 2016;22:8026-40.
14. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 2012;122:1377-92.
15. Sanajou D, Haghjo AG, Argani H, Roshangar L, Ahmad SNS, Jigheh ZA, et al. FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats. J Physiol Biochem 2018;74:467-78.
16. Sanajou D, Haghjo AG, Argani H, Roshangar L, Rashtchizadeh N, Ahmad SNS, et al., Reduction of renal tubular injury with a RAGE inhibitor FPS-ZM1, valsartan and their combination in streptozotocin-induced diabetes in the rat. Eur J Pharmacol 2019;842:40-8.
17. Sanajou D, Haghjo AG, Argani H, Aslani S. AGE-RAGE axis blockade in diabetic nephropathy: Current status and future directions. Eur J Pharmacol 2018;833:158-64.
18. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 1988;37:1163-7.
19. Winzell MS, Ahrén B. The high-fat diet–fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 2004;53:215-9.
20. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014;18:1-14.
21. Patel R, Baker SS, Liu W, Desai S, Alkhouri R, Kozielski R, et al. Effect of dietary advanced glycation end products on mouse liver. PLoS One 2012;7:e35143.
22. Ribeiro CT, Gasparotto J, Teixeira AA, Portela LVC, Flores VNL, Moreira JCF, et al. Immune neutralization of the receptor for advanced glycation endproducts reduce liver oxidative damage induced by an acute systemic injection of lipopolysaccharide. J Biochem 2018;163:515-23.
23. Sharma I, Tupe RS, Wallner AK, Kanwar YS. Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy. Am J Physiol Renal Physiol 2018;314:F107-21.
24. Lee H, Park JR, Kim WJ, Sundar IK, Rahman I, Park SM, et al. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signalling. FASEB J 2017;31:2076-89.
25. Shen C, Ma Y, Zeng Z, Yin Q, Hong Y, Hou X, et al. RAGE-specific inhibitor FPS-ZM1 attenuates AGEs-induced neuroinflammation and oxidative stress in rat primary microglia. Neurochem Res 2017;42:2902-11.
26. Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin resistance and type 2 diabetes in high-fat–fed mice are linked to high glycotoxin intake. Diabetes 2005;54:2314-9.
27. Jones A, Hattersley A. The clinical utility of C‐peptide measurement in the care of patients with diabetes. Diabetic Med 2013;30:803-17.
28. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012;122:1574-83.
29. Vaubourdolle M, Chazouillères O, Briaud I, Legendre C, Serfaty L, Poupon R, et al. Plasma alpha-glutathione S-transferase assessed as a marker of liver damage in patients with chronic hepatitis C. Clin Chem 1995;41:1716-19.
30. Matsumoto R, Watanabe S, Beppu T, Futagawa S. Serum alpha-glutathione S-transferase: a new marker of hepatocellular damage associated with hepatectomy. Hepatol Res 2000;18:10-8.
31. Federico A, Tuccillo C, Crafa E, Loguercio C. The significance of alpha-glutathione S-transferase determination in patients with chronic liver diseases. Minerva Gastroenterol Dietol 1999;45:181-5.
32. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander‐Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012;55:77-85.
33. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin‐18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009;50:1072-78.
34. Takeuchi-Yorimoto A, Yamaura Y, Kanki M, Ide T, Nakata A, Noto T, et al. MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease. Toxicol Lett 2016;258:159-67.
35. Benhamouche-Trouillet S, Postic C. Emerging role of miR-21 in non-alcoholic fatty liver disease. Gut 2016;65:1781-3.
36. Park D, Jo IG, Jang JY, Kwak TH, Yoo SK, Jeon JH, et al. A Dunnione Compound MB12662 Improves Cisplatin-Induced Tissue Injury and Emesis. Biomol Ther(Seoul) 2015;23:449-57.
37. Wu H, Ng R, Chen X, Steer CJ, Song G. MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway. Gut 2016;65:1850-60.
2. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012;56:943-51.
3. Cobbina E, Akhlaghi F. Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters. Drug Metab Rev 2017;49:197-211.
4. Alkassabany YM, Farghaly AG, El-Ghitany EM. Prevalence, risk factors, and predictors of nonalcoholic fatty liver disease among schoolchildren: a hospital-based study in Alexandria, Egypt. Arab J Gastroenterol 2014;15:76-81.
5. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013;10:627-6.
6. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-307.
7. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85.
8. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-90.
9. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016;65:369-76.
10. Dajani AI, Abu Hammour AM, Zakaria MA, Al Jaberi MR, Nounou MA, Semrin AI. Essential phospholipids as a supportive adjunct to the management of patients with primary NAFLD and NAFLD associated with type 2 diabetes mellitus or hyperlipidaemia. Hepatol Int 2013;7:748-54.
11. Mohamed WS, Mostafa AM, Mohamed JM, Serwah AH. Effects of fenugreek, Nigella, and termis seeds in nonalcoholic fatty liver in obese diabetic albino rats. Arab J Gastroenterol 2015;16:1-9.
12. Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Ueda T, Tsutsumi M, et al. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies. World J Hepatol 2014;6:880-93.
13. Leung C, Herath BC, Jia Z, Andrikopoulos S, Brown BE, Davies MJ, et al. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease. World J Gastroenterol 2016;22:8026-40.
14. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 2012;122:1377-92.
15. Sanajou D, Haghjo AG, Argani H, Roshangar L, Ahmad SNS, Jigheh ZA, et al. FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats. J Physiol Biochem 2018;74:467-78.
16. Sanajou D, Haghjo AG, Argani H, Roshangar L, Rashtchizadeh N, Ahmad SNS, et al., Reduction of renal tubular injury with a RAGE inhibitor FPS-ZM1, valsartan and their combination in streptozotocin-induced diabetes in the rat. Eur J Pharmacol 2019;842:40-8.
17. Sanajou D, Haghjo AG, Argani H, Aslani S. AGE-RAGE axis blockade in diabetic nephropathy: Current status and future directions. Eur J Pharmacol 2018;833:158-64.
18. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 1988;37:1163-7.
19. Winzell MS, Ahrén B. The high-fat diet–fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 2004;53:215-9.
20. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014;18:1-14.
21. Patel R, Baker SS, Liu W, Desai S, Alkhouri R, Kozielski R, et al. Effect of dietary advanced glycation end products on mouse liver. PLoS One 2012;7:e35143.
22. Ribeiro CT, Gasparotto J, Teixeira AA, Portela LVC, Flores VNL, Moreira JCF, et al. Immune neutralization of the receptor for advanced glycation endproducts reduce liver oxidative damage induced by an acute systemic injection of lipopolysaccharide. J Biochem 2018;163:515-23.
23. Sharma I, Tupe RS, Wallner AK, Kanwar YS. Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy. Am J Physiol Renal Physiol 2018;314:F107-21.
24. Lee H, Park JR, Kim WJ, Sundar IK, Rahman I, Park SM, et al. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signalling. FASEB J 2017;31:2076-89.
25. Shen C, Ma Y, Zeng Z, Yin Q, Hong Y, Hou X, et al. RAGE-specific inhibitor FPS-ZM1 attenuates AGEs-induced neuroinflammation and oxidative stress in rat primary microglia. Neurochem Res 2017;42:2902-11.
26. Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin resistance and type 2 diabetes in high-fat–fed mice are linked to high glycotoxin intake. Diabetes 2005;54:2314-9.
27. Jones A, Hattersley A. The clinical utility of C‐peptide measurement in the care of patients with diabetes. Diabetic Med 2013;30:803-17.
28. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012;122:1574-83.
29. Vaubourdolle M, Chazouillères O, Briaud I, Legendre C, Serfaty L, Poupon R, et al. Plasma alpha-glutathione S-transferase assessed as a marker of liver damage in patients with chronic hepatitis C. Clin Chem 1995;41:1716-19.
30. Matsumoto R, Watanabe S, Beppu T, Futagawa S. Serum alpha-glutathione S-transferase: a new marker of hepatocellular damage associated with hepatectomy. Hepatol Res 2000;18:10-8.
31. Federico A, Tuccillo C, Crafa E, Loguercio C. The significance of alpha-glutathione S-transferase determination in patients with chronic liver diseases. Minerva Gastroenterol Dietol 1999;45:181-5.
32. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander‐Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012;55:77-85.
33. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin‐18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009;50:1072-78.
34. Takeuchi-Yorimoto A, Yamaura Y, Kanki M, Ide T, Nakata A, Noto T, et al. MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease. Toxicol Lett 2016;258:159-67.
35. Benhamouche-Trouillet S, Postic C. Emerging role of miR-21 in non-alcoholic fatty liver disease. Gut 2016;65:1781-3.
36. Park D, Jo IG, Jang JY, Kwak TH, Yoo SK, Jeon JH, et al. A Dunnione Compound MB12662 Improves Cisplatin-Induced Tissue Injury and Emesis. Biomol Ther(Seoul) 2015;23:449-57.
37. Wu H, Ng R, Chen X, Steer CJ, Song G. MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway. Gut 2016;65:1850-60.
| Files | ||
| Issue | Vol 60, No 1 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/acta.v60i1.8326 | |
| Keywords | ||
| Diabetes FPS-ZM1 Liver injury Receptor for advanced glycation end products | ||
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How to Cite
1.
Aslani S, Bahrambeigi S, Sanajou D. FPS-ZM1 Alleviates Circulating Indices of Liver Injury in Diet-Induced Type 2 Diabetic Mice. Acta Med Iran. 2022;60(1):40-45.
