Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

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Author(s)

    • Miyashita Taishi
    • Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University
    • Toyoda Yasuyuki
    • Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University
    • Tsuneyama Koichi
    • Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research,University of Toyama,
    • Fukami Tatsuki
    • Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University
    • Nakajima Miki
    • Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University
    • Yokoi Tsuyoshi
    • Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

Journal

  • The Journal of Toxicological Sciences

    The Journal of Toxicological Sciences 37(5), 931-942, 2012

    The Japanese Society of Toxicology

Codes

  • NII Article ID (NAID)
    130004447006
  • Text Lang
    ENG
  • ISSN
    0388-1350
  • Data Source
    J-STAGE 
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