Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver

Motoyuki Kohjima, Tsuyoshi Yoshimoto, Munechika Enjoji, Nobuyoshi Fukushima, Kunitaka Fukuizumi, Tsukasa Nakamura, Miho Kurokawa, Nao Fujimori, Yusuke Sasaki, Yasushi Shimonaka, Yusuke Murata, Susumu Koyama, Ken Kawabe, Kazuhiro Haraguchi, Yorinobu Sumida, Naohiko Harada, Masaki Kato, Kazuhiro Kotoh, Makoto Nakamuta

Research output: Contribution to journalArticle

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Abstract

AIM: To investigate the relationship between the ironmetabolismrelated gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients. METHODS: The hepatic expression profile of ironmetabolismrelated genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolismrelated genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry. RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes. CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.

Original languageEnglish
Pages (from-to)3291-3299
Number of pages9
JournalWorld Journal of Gastroenterology
Volume21
Issue number11
DOIs
Publication statusPublished - Jan 1 2015

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Hepcidins
Ribavirin
Hepacivirus
Interferons
Iron
Liver
Chronic Hepatitis C
Virus Diseases
Transcriptome
Iron Regulatory Protein 2
Hepatocytes
Iron Regulatory Protein 1
Gene Expression
Transferrin Receptors
Iron Overload
Electrospray Ionization Mass Spectrometry
Living Donors
Transferrin
Virus Replication
Tandem Mass Spectrometry

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver. / Kohjima, Motoyuki; Yoshimoto, Tsuyoshi; Enjoji, Munechika; Fukushima, Nobuyoshi; Fukuizumi, Kunitaka; Nakamura, Tsukasa; Kurokawa, Miho; Fujimori, Nao; Sasaki, Yusuke; Shimonaka, Yasushi; Murata, Yusuke; Koyama, Susumu; Kawabe, Ken; Haraguchi, Kazuhiro; Sumida, Yorinobu; Harada, Naohiko; Kato, Masaki; Kotoh, Kazuhiro; Nakamuta, Makoto.

In: World Journal of Gastroenterology, Vol. 21, No. 11, 01.01.2015, p. 3291-3299.

Research output: Contribution to journalArticle

Kohjima, M, Yoshimoto, T, Enjoji, M, Fukushima, N, Fukuizumi, K, Nakamura, T, Kurokawa, M, Fujimori, N, Sasaki, Y, Shimonaka, Y, Murata, Y, Koyama, S, Kawabe, K, Haraguchi, K, Sumida, Y, Harada, N, Kato, M, Kotoh, K & Nakamuta, M 2015, 'Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver', World Journal of Gastroenterology, vol. 21, no. 11, pp. 3291-3299. https://doi.org/10.3748/wjg.v21.i11.3291
Kohjima, Motoyuki ; Yoshimoto, Tsuyoshi ; Enjoji, Munechika ; Fukushima, Nobuyoshi ; Fukuizumi, Kunitaka ; Nakamura, Tsukasa ; Kurokawa, Miho ; Fujimori, Nao ; Sasaki, Yusuke ; Shimonaka, Yasushi ; Murata, Yusuke ; Koyama, Susumu ; Kawabe, Ken ; Haraguchi, Kazuhiro ; Sumida, Yorinobu ; Harada, Naohiko ; Kato, Masaki ; Kotoh, Kazuhiro ; Nakamuta, Makoto. / Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver. In: World Journal of Gastroenterology. 2015 ; Vol. 21, No. 11. pp. 3291-3299.
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AU - Kohjima, Motoyuki

AU - Yoshimoto, Tsuyoshi

AU - Enjoji, Munechika

AU - Fukushima, Nobuyoshi

AU - Fukuizumi, Kunitaka

AU - Nakamura, Tsukasa

AU - Kurokawa, Miho

AU - Fujimori, Nao

AU - Sasaki, Yusuke

AU - Shimonaka, Yasushi

AU - Murata, Yusuke

AU - Koyama, Susumu

AU - Kawabe, Ken

AU - Haraguchi, Kazuhiro

AU - Sumida, Yorinobu

AU - Harada, Naohiko

AU - Kato, Masaki

AU - Kotoh, Kazuhiro

AU - Nakamuta, Makoto

PY - 2015/1/1

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N2 - AIM: To investigate the relationship between the ironmetabolismrelated gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients. METHODS: The hepatic expression profile of ironmetabolismrelated genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolismrelated genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry. RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes. CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.

AB - AIM: To investigate the relationship between the ironmetabolismrelated gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients. METHODS: The hepatic expression profile of ironmetabolismrelated genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolismrelated genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry. RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes. CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.

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