Dietary Iron Overload Abrogates Chemically-Induced Liver Cirrhosis in Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Biochemical Analyses
2.3. Histopathology
2.4. Immunohistochemistry
2.5. Western Blot
2.6. Statistical Analysis
3. Results
3.1. Dietary Iron Overload Abrogates the Pathological Phenotype of Chemically Induced Liver Cirrhosis
3.1.1. Biochemical Findings
3.1.2. Pathological Findings
3.2. The Abrogation of Liver Cirrhosis by Dietary Iron Overload Is More Related to Changes in Apoptosis Than in Xenobiotic Metabolism and Oxidative Stress
3.2.1. Changes in Thioacetamide (TAA)-Metabolizing Enzymes
3.2.2. Changes in Oxidative Stress
3.2.3. Changes in Cell Death
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CLD | chronic liver disease |
HCC | hepatocellular carcinoma |
ROS | reactive oxygen species |
NAFLD | non-alcoholic fatty liver disease |
TAA | thioacetamide |
TBARS | thiobarbituric acid reacting substances |
PBS | phosphate buffered saline |
TUNEL | terminal deoxynucleotidyl transferase dUTP nick end labeling |
CYP | cytochrome P450 |
FMO | flavin containing monooxygenase |
p-RIP3 | phosphorylated receptor interacting protein 3 |
Bax | B-cell lymphoma protein 2-associated X |
VDAC1 | voltage-dependent anion-selective channel protein 1 |
ALT | alanine aminotransferase |
AST | aspartate aminotransferase |
HSC | hepatic stellate cell |
References
- Heimbach, J.K.; Kulik, L.M.; Finn, R.S.; Sirlin, C.B.; Abecassis, M.M.; Roberts, L.R.; Zhu, A.X.; Murad, M.H.; Marrero, J.A. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018, 67, 358–380. [Google Scholar] [CrossRef] [PubMed]
- Mokdad, A.A.; Lopez, A.D.; Shahraz, S.; Lozano, R.; Mokdad, A.H.; Stanaway, J.; Murray, C.J.; Naghavi, M. Liver cirrhosis mortality in 187 countries between 1980 and 2010: A systematic analysis. BMC Med. 2014, 12, 145. [Google Scholar] [CrossRef] [PubMed]
- Milic, S.; Mikolasevic, I.; Orlic, L.; Devcic, E.; Starcevic-Cizmarevic, N.; Stimac, D.; Kapovic, M.; Ristic, S. The Role of Iron and Iron Overload in Chronic Liver Disease. Med. Sci. Monit. 2016, 22, 2144–2151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pietrangelo, A. Iron and the liver. Liver Int. 2016, 36 (Suppl. 1), 116–123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brissot, P.; Loreal, O. Iron metabolism and related genetic diseases: A cleared land, keeping mysteries. J. Hepatol. 2016, 64, 505–515. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Knutson, M.D. Iron transport proteins: Gateways of cellular and systemic iron homeostasis. J. Biol. Chem. 2017, 292, 12735–12743. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Munoz, M.; Garcia-Erce, J.A.; Remacha, A.F. Disorders of iron metabolism. Part 1: Molecular basis of iron homoeostasis. J. Clin. Pathol. 2011, 64, 281–286. [Google Scholar] [CrossRef] [PubMed]
- Maras, J.S.; Maiwall, R.; Harsha, H.C.; Das, S.; Hussain, M.S.; Kumar, C.; Bihari, C.; Rastogi, A.; Kumar, M.; Trehanpati, N.; et al. Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute-on-chronic liver failure. Hepatology 2015, 61, 1306–1320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Philippe, M.A.; Ruddell, R.G.; Ramm, G.A. Role of iron in hepatic fibrosis: One piece in the puzzle. World J. Gastroenterol. 2007, 13, 4746–4754. [Google Scholar] [CrossRef] [PubMed]
- Guyader, D.; Thirouard, A.S.; Erdtmann, L.; Rakba, N.; Jacquelinet, S.; Danielou, H.; Perrin, M.; Jouanolle, A.M.; Brissot, P.; Deugnier, Y. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J. Hepatol. 2007, 46, 587–595. [Google Scholar] [CrossRef] [PubMed]
- Nelson, J.E.; Wilson, L.; Brunt, E.M.; Yeh, M.M.; Kleiner, D.E.; Unalp-Arida, A.; Kowdley, K.V.; Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011, 53, 448–457. [Google Scholar] [CrossRef] [PubMed]
- Sebastiani, G.; Tempesta, D.; Alberti, A. Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus. J. Viral Hepat. 2012, 19, e170–e176. [Google Scholar] [CrossRef] [PubMed]
- Lambrecht, R.W.; Sterling, R.K.; Naishadham, D.; Stoddard, A.M.; Rogers, T.; Morishima, C.; Morgan, T.R.; Bonkovsky, H.L.; Group, H.-C.T. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 2011, 140, 1490–1500.e3. [Google Scholar] [CrossRef] [PubMed]
- Maliken, B.D.; Nelson, J.E.; Klintworth, H.M.; Beauchamp, M.; Yeh, M.M.; Kowdley, K.V. Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology 2013, 57, 1806–1813. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Izawa, T.; Murakami, H.; Wijesundera, K.K.; Golbar, H.M.; Kuwamura, M.; Yamate, J. Inflammatory regulation of iron metabolism during thioacetamide-induced acute liver injury in rats. Exp. Toxicol. Pathol. 2014, 66, 155–162. [Google Scholar] [CrossRef] [PubMed]
- Wijesundera, K.K.; Izawa, T.; Tennakoon, A.H.; Murakami, H.; Golbar, H.M.; Katou-Ichikawa, C.; Tanaka, M.; Kuwamura, M.; Yamate, J. M1- and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide (TAA), focusing on Iba1 and galectin-3. Exp. Mol. Pathol. 2014, 96, 382–392. [Google Scholar] [CrossRef] [PubMed]
- Tennakoon, A.H.; Izawa, T.; Wijesundera, K.K.; Katou-Ichikawa, C.; Tanaka, M.; Golbar, H.M.; Kuwamura, M.; Yamate, J. Analysis of glial fibrillary acidic protein (GFAP)-expressing ductular cells in a rat liver cirrhosis model induced by repeated injections of thioacetamide (TAA). Exp. Mol. Pathol. 2015, 98, 476–485. [Google Scholar] [CrossRef] [PubMed]
- Tennakoon, A.H.; Izawa, T.; Wijesundera, K.K.; Murakami, H.; Katou-Ichikawa, C.; Tanaka, M.; Golbar, H.M.; Kuwamura, M.; Yamate, J. Immunohistochemical characterization of glial fibrillary acidic protein (GFAP)-expressing cells in a rat liver cirrhosis model induced by repeated injections of thioacetamide (TAA). Exp. Toxicol. Pathol. 2015, 67, 53–63. [Google Scholar] [CrossRef] [PubMed]
- Wijesundera, K.K.; Izawa, T.; Tennakoon, A.H.; Golbar, H.M.; Tanaka, M.; Kuwamura, M.; Yamate, J. M1-/M2-macrophages contribute to the development of GST-P-positive preneoplastic lesions in chemically-induced rat cirrhosis. Exp. Toxicol. Pathol. 2015, 67, 467–475. [Google Scholar] [CrossRef] [PubMed]
- Wijesundera, K.K.; Izawa, T.; Tennakoon, A.H.; Golbar, H.M.; Tanaka, M.; Kuwamura, M.; Yamate, J. M1-/M2-macrophage polarization in pseudolobules consisting of adipohilin-rich hepatocytes in thioacetamide (TAA)-induced rat hepatic cirrhosis. Exp. Mol. Pathol. 2016, 101, 133–142. [Google Scholar] [CrossRef] [PubMed]
- Atarashi, M.; Izawa, T.; Miyagi, R.; Ohji, S.; Hashimoto, A.; Kuwamura, M.; Yamate, J. Dietary iron supplementation alters hepatic inflammation in a rat model of nonalcoholic steatohepatitis. Nutrients 2018, 10, 175. [Google Scholar] [CrossRef] [PubMed]
- Kang, J.S.; Wanibuchi, H.; Morimura, K.; Wongpoomchai, R.; Chusiri, Y.; Gonzalez, F.J.; Fukushima, S. Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity. Toxicol. Appl. Pharmacol. 2008, 228, 295–300. [Google Scholar] [CrossRef] [PubMed]
- Hajovsky, H.; Hu, G.; Koen, Y.; Sarma, D.; Cui, W.; Moore, D.S.; Staudinger, J.L.; Hanzlik, R.P. Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem. Res. Toxicol. 2012, 25, 1955–1963. [Google Scholar] [CrossRef] [PubMed]
- Ripp, S.L.; Itagaki, K.; Philpot, R.M.; Elfarra, A.A. Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes. Drug Metab. Dispos. Boil. Fate Chem. 1999, 27, 46–52. [Google Scholar]
- Yamazaki, M.; Shimizu, M.; Uno, Y.; Yamazaki, H. Drug oxygenation activities mediated by liver microsomal flavin-containing monooxygenases 1 and 3 in humans, monkeys, rats, and minipigs. Biochem. Pharmacol. 2014, 90, 159–165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fernandes-Alnemri, T.; Litwack, G.; Alnemri, E.S. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J. Biol. Chem. 1994, 269, 30761–30764. [Google Scholar] [PubMed]
- Westphal, D.; Dewson, G.; Czabotar, P.E.; Kluck, R.M. Molecular biology of Bax and Bak activation and action. Biochim. Biophys. Acta 2011, 1813, 521–531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, D.W.; Shao, J.; Lin, J.; Zhang, N.; Lu, B.J.; Lin, S.C.; Dong, M.Q.; Han, J. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009, 325, 332–336. [Google Scholar] [CrossRef] [PubMed]
- Arezzini, B.; Lunghi, B.; Lungarella, G.; Gardi, C. Iron overload enhances the development of experimental liver cirrhosis in mice. Int. J. Biochem. Cell Biol. 2003, 35, 486–495. [Google Scholar] [CrossRef]
- Pietrangelo, A. Mechanisms of iron hepatotoxicity. J. Hepatol. 2016, 65, 226–227. [Google Scholar] [CrossRef] [PubMed]
- Dixon, S.J.; Stockwell, B.R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 2014, 10, 9–17. [Google Scholar] [CrossRef] [PubMed]
- Bogdan, A.R.; Miyazawa, M.; Hashimoto, K.; Tsuji, Y. Regulators of iron homeostasis: New players in metabolism, cell death, and disease. Trends Biochem. Sci. 2016, 41, 274–286. [Google Scholar] [CrossRef] [PubMed]
- Bulvik, B.E.; Berenshtein, E.; Meyron-Holtz, E.G.; Konijn, A.M.; Chevion, M. Cardiac protection by preconditioning is generated via an iron-signal created by proteasomal degradation of iron proteins. PLoS ONE 2012, 7, e48947. [Google Scholar] [CrossRef] [PubMed]
- Eid, R.; Arab, N.T.; Greenwood, M.T. Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms. Biochim. Biophys. Acta 2017, 1864, 399–430. [Google Scholar] [CrossRef] [PubMed]
- Munoz, J.P.; Chiong, M.; Garcia, L.; Troncoso, R.; Toro, B.; Pedrozo, Z.; Diaz-Elizondo, J.; Salas, D.; Parra, V.; Nunez, M.T.; et al. Iron induces protection and necrosis in cultured cardiomyocytes: Role of reactive oxygen species and nitric oxide. Free Radic. Biol. Med. 2010, 48, 526–534. [Google Scholar] [CrossRef] [PubMed]
- White, A.R.; Barnham, K.J.; Huang, X.; Voltakis, I.; Beyreuther, K.; Masters, C.L.; Cherny, R.A.; Bush, A.I.; Cappai, R. Iron inhibits neurotoxicity induced by trace copper and biological reductants. J. Biol. Inorg. Chem. 2004, 9, 269–280. [Google Scholar] [CrossRef] [PubMed]
- Lunova, M.; Goehring, C.; Kuscuoglu, D.; Mueller, K.; Chen, Y.; Walther, P.; Deschemin, J.C.; Vaulont, S.; Haybaeck, J.; Lackner, C.; et al. Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload. J. Hepatol. 2014, 61, 633–641. [Google Scholar] [CrossRef] [PubMed]
- Silva-Gomes, S.; Santos, A.G.; Caldas, C.; Silva, C.M.; Neves, J.V.; Lopes, J.; Carneiro, F.; Rodrigues, P.N.; Duarte, T.L. Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death. J. Hepatol. 2014, 60, 354–361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, H.; An, P.; Xie, E.; Wu, Q.; Fang, X.; Gao, H.; Zhang, Z.; Li, Y.; Wang, X.; Zhang, J.; et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 2017, 66, 449–465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ledda-Columbano, G.M.; Coni, P.; Curto, M.; Giacomini, L.; Faa, G.; Oliverio, S.; Piacentini, M.; Columbano, A. Induction of two different modes of cell death, apoptosis and necrosis, in rat liver after a single dose of thioacetamide. Am. J. Pathol. 1991, 139, 1099–1109. [Google Scholar] [PubMed]
- Hsu, D.Z.; Chu, P.Y.; Li, Y.H.; Chandrasekaran, V.R.; Liu, M.Y. Role of flavin-containing-monooxygenase-dependent neutrophil activation in thioacetamide-induced hepatic inflammation in rats. Toxicology 2012, 298, 52–58. [Google Scholar] [CrossRef] [PubMed]
- Lu, Y.; Wang, X.; Cederbaum, A.I. Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G308–G319. [Google Scholar] [CrossRef] [PubMed]
- Weltman, M.D.; Farrell, G.C.; Liddle, C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 1996, 111, 1645–1653. [Google Scholar] [CrossRef]
- Kawada, N.; Kristensen, D.B.; Asahina, K.; Nakatani, K.; Minamiyama, Y.; Seki, S.; Yoshizato, K. Characterization of a stellate cell activation-associated protein (STAP) with peroxidase activity found in rat hepatic stellate cells. J. Biol. Chem. 2001, 276, 25318–25323. [Google Scholar] [CrossRef] [PubMed]
- Sugimoto, H.; Makino, M.; Sawai, H.; Kawada, N.; Yoshizato, K.; Shiro, Y. Structural basis of human cytoglobin for ligand binding. J. Mol. Biol. 2004, 339, 873–885. [Google Scholar] [CrossRef] [PubMed]
- Xu, R.; Harrison, P.M.; Chen, M.; Li, L.; Tsui, T.Y.; Fung, P.C.; Cheung, P.T.; Wang, G.; Li, H.; Diao, Y.; et al. Cytoglobin overexpression protects against damage-induced fibrosis. Mol. Ther. 2006, 13, 1093–1100. [Google Scholar] [CrossRef] [PubMed]
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Atarashi, M.; Izawa, T.; Mori, M.; Inai, Y.; Kuwamura, M.; Yamate, J. Dietary Iron Overload Abrogates Chemically-Induced Liver Cirrhosis in Rats. Nutrients 2018, 10, 1400. https://doi.org/10.3390/nu10101400
Atarashi M, Izawa T, Mori M, Inai Y, Kuwamura M, Yamate J. Dietary Iron Overload Abrogates Chemically-Induced Liver Cirrhosis in Rats. Nutrients. 2018; 10(10):1400. https://doi.org/10.3390/nu10101400
Chicago/Turabian StyleAtarashi, Machi, Takeshi Izawa, Mutsuki Mori, Yohei Inai, Mitsuru Kuwamura, and Jyoji Yamate. 2018. "Dietary Iron Overload Abrogates Chemically-Induced Liver Cirrhosis in Rats" Nutrients 10, no. 10: 1400. https://doi.org/10.3390/nu10101400