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Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells

  • Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Advanced glycation end products (AGEs), final reaction products of protein with sugars, are known to contribute to diabetes-related complications. We have recently demonstrated high levels of serum AGEs in patients with nonalcoholic steatohepatitis (NASH). However, direct evidence for the participation of AGEs in hepatic infl ammation and fibrosis has not been shown. To explore the pathogenesis of NASH, we examined the biological infl uence of AGEs on hepatic stellate cells (HSCs) in vitro.

Methods

An established human HSC line, LI90, was exposed to a glyceraldehyde-derived-AGE (glycer-AGE), and the phenotypical changes of the LI90 cells were investigated. Intracellular formation of reactive oxygen species (ROS) was measured using a fl uorescent probe. Cell proliferation was examined by MTS assay. Fibrogenic marker gene expression was analyzed by quantitative real-time polymerase chain reaction. The production of monocyte chemoattractant protein 1 (MCP-1) was assessed by enzyme-linked immunosorbent assay.

Results

The expression of AGE receptor was confirmed in LI90 cells at the mRNA and protein levels. In addition to increasing intracellular ROS generation, glycer-AGE upregulated fibrogenic genes such as those encoding for α-smooth muscle actin, transforming growth factor-β1, and collagen type Iα2. The expression of MCP-1 mRNA in LI90 cells as well as its secretion into the culture medium was significantly increased in response to AGEs. These changes were attenuated by treatment with the antioxidant N-acetylcysteine.

Conclusions

These data indicate that AGEs induce ROS generation and intensify the proliferation and activation of HSCs, supporting the possibility that antioxidants may represent a promising treatment for prevention of the development of hepatic fibrosis in NASH.

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Authors and Affiliations

  1. Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    Keiko Iwamoto, Hideyuki Hyogo & Kazuaki Chayama

  2. Department of General Medicine, Division of Clinical Pharmacotherapeutics, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Keishi Kanno & Susumu Tazuma

  3. Department of Internal Medicine III, Kurume University School of Medicine, Fukuoka, Japan

    Sho-Ichi Yamagishi

  4. Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan

    Masayoshi Takeuchi

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  1. Keiko Iwamoto
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Iwamoto, K., Kanno, K., Hyogo, H. et al. Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells. J Gastroenterol 43, 298–304 (2008). https://doi.org/10.1007/s00535-007-2152-7

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  • DOI: https://doi.org/10.1007/s00535-007-2152-7

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