Hypercholesterolemia in rats with hepatomas: Increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol

Authors

  • Takeshi Hirayama,

    1. Division of Gastroenterology and Hepatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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    • T. Hirayama and A. Honda contributed equally to this work.

  • Akira Honda,

    1. Division of Gastroenterology and Hepatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    2. Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki, Japan
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    • T. Hirayama and A. Honda contributed equally to this work.

  • Yasushi Matsuzaki,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    2. Division of Gastroenterology and Hepatology, Tokyo Medical University, Kasumigaura Hospital, Ami, Ibaraki, Japan
    • Division of Gastroenterology and Hepatology, Tokyo Medical University, Kasumigaura Hospital, 3-20-1 Ami-Machi-Chuoh, Inashikigun, Ibaraki 300-0395, Japan
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    • fax: (81) 29-888-3463

  • Teruo Miyazaki,

    1. Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki, Japan
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  • Tadashi Ikegami,

    1. Division of Gastroenterology and Hepatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    2. Division of Gastroenterology and Hepatology, Tokyo Medical University, Kasumigaura Hospital, Ami, Ibaraki, Japan
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  • Mikio Doy,

    1. Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki, Japan
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  • Guorong Xu,

    1. Department of Medicine, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, NJ
    2. Veterans Affairs Medical Center, East Orange, NJ
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  • Michael Lea,

    1. Department of Medicine, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, NJ
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  • Gerald Salen

    1. Department of Medicine, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, NJ
    2. Veterans Affairs Medical Center, East Orange, NJ
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  • Potential conflict of interest: Nothing to report.

Abstract

Hypercholesterolemia is an important paraneoplastic syndrome in patients with hepatoma, but the nature of this defect has not yet been identified. We investigated the molecular mechanisms of hypercholesterolemia in a hepatoma-bearing rat model. Buffalo rats were implanted in both flanks with Morris hepatoma 7777 (McA-RH7777) cells. After 4 weeks, tumor weight was 5.5 ± 1.7 g, and serum cholesterol level increased from 60 ± 2 to 90 ± 2 mg/dL. Protein and mRNA expression of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) was markedly higher in tumors than in livers. These increases were associated with activation of liver X receptor α (LXRα) as a result of the increased tissue oxysterol concentrations. The accumulation of oxysterols in the hepatomas appeared to be caused mainly by the upregulation of cholesterol biosynthesis, despite the increased tissue sterol concentrations. Overexpression of the sterol regulatory element-binding protein (SREBP) processing system relative to sterol concentration contributed to the resistance to sterols in this tumor. In addition, bile acid biosynthesis was inhibited despite the reduced expression of the small heterodimer partner (SHP) and activated LXRα, which also appeared to contribute to the accumulation of oxysterols followed by the acceleration of cholesterol efflux. In conclusion, hypercholesterolemia in McA-RH7777 hepatoma-bearing rats was caused by increased cholesterol efflux from tumors as a result of activation of LXRα. Overexpression of the SREBP processing system contributed to the activation of LXRα by maintaining high oxysterol levels in tissue. (HEPATOLOGY 2006.)

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