Ethanol Induces Transforming Growth Factor-α Expression in Hepatocytes, Leading to Stimulation of Collagen Synthesis by Hepatic Stellate Cells

Authors

  • Junji Kato,

    Corresponding author
    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
      Junji Kato, MD, PhD, Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan; Fax: 81-11-612-7987; E-mail: jkato@sapmed.ac.jp.
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  • Yasuhiro Sato,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Noriaki Inui,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Yoichiro Nakano,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Rishu Takimoto,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Kohich Takada,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Masayoshi Kobune,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Ganji Kuroiwa,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Sachie Miyake,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Yutaka Kohgo,

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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  • Yoshiro Niitsu

    1. Fourth Department of Internal Medicine (JK, YS, NI, YN, RT, KT, MK, GK, SM, YN), Sapporo Medical University School of Medicine, Sapporo; and Third Department of Internal Medicine (YK), Asahikawa Medical College, Asahikawa, Japan.
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Junji Kato, MD, PhD, Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan; Fax: 81-11-612-7987; E-mail: jkato@sapmed.ac.jp.

Abstract

Background: Liver fibrosis often develops in alcoholic liver diseases without accompanying inflammation; however, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for alcoholic liver diseases, we previously found that ethanol exposure causes HepG2 cells to secrete a ∼6000 Da nonheparin-binding polypeptide that stimulates collagen synthesis in human IMR-90 fibroblasts. The aim of the current study was to characterize and identify this factor.

Methods: Concentration of type I procollagen peptide and transforming growth factor (TGF)-α was assessed by enzyme-linked immunosorbent assay. TGF-α protein expression was examined by Western blot. Type I collagen messenger RNA expression in rat hepatic stellate cells was assessed by reverse transcription-polymerase chain reaction.

Results: The collagen-stimulating activity in conditioned media from ethanol-exposed HepG2 cells to stimulate type I procollagen peptide synthesis of IMR-90 cells was specifically inhibited by addition of anti-TGF-α antibodies. Western blot analysis showed increased TGF-α protein expression in ethanol-treated HepG2 cells. TGF-α in conditioned medium from ethanol-exposed HepG2 cells stimulated type-I collagen messenger RNA expression in rat hepatic stellate cells.

Conclusions: These results suggest that TGF-α derived from ethanol-exposed hepatocytes may contribute to the development of hepatic fibrosis in alcoholic liver diseases.

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