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HIF-1α Expression as a Protective Strategy of HepG2 Cells Against Fatty Acid-Induced Toxicity

Authors

  • Wonbaek Yoo,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
    2. Graduate School of Medicine, Korea University, Seoul, Republic of Korea
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  • Kyung Hee Noh,

    1. Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea
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  • Jae Hee Ahn,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Ji Hee Yu,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Ji A. Seo,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Sin Gon Kim,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Kyung Mook Choi,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Sei Hyun Baik,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Dong Seop Choi,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Tae Woo Kim,

    1. Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea
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  • Hyo Joon Kim,

    1. Department of Molecular & Life Science, College of Science & Technology, Hanyang University-ERICA, Ansan, Republic of Korea
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  • Nan Hee Kim

    Corresponding author
    1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
    • Correspondence to: Prof. Nan Hee Kim, MD, PhD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, 516 Gojan-1-dong, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Republic of Korea.

      E-mail: nhkendo@gmail.com

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  • The authors declared that they have no conflicts of interest.

ABSTRACT

Free fatty acid-induced lipotoxicity via increased endoplasmic reticulum (ER) stress and hepatocyte apoptosis is a key pathological mechanism of non-alcoholic steatohepatitis. A role of hypoxia-inducible factor 1α (HIF-1α) in this process has been suggested, but direct evidence is lacking. Here, we used HepG2 cells as a model to study whether HIF-1α can reduce palmitic acid-induced lipotoxicity and ER stress. In HepG2 cells treated with 500 µM palmitic acid, HIF-1α expression increased transiently, the decline was associated with increased cleaved caspase-3 expression. Overexpression and knockdown of HIF-1α decreased and exacerbated, respectively, palmitic acid-induced lipoapoptosis. The overexpression also blunted upregulation of the ER stress markers, C/EBP homologous protein (CHOP) and chaperone immunoglobulin heavy chain binding protein (Bip), while the knockdown increased the level of CHOP. In line with this, CHOP promoter activity decreased following HIF-1α binding to the CHOP promoter hypoxia response element. These results indicate that hepatocyte lipotoxicity is associated with decreased HIF-1α expression. It also suggests that upregulation of HIF-1α can be a possible strategy to reduce lipotoxicity in non-alcoholic fatty liver disease. J. Cell. Biochem. 115: 1147–1158, 2014. © 2014 Wiley Periodicals, Inc.

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