• Open Access

Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor

Authors

  • Hyunsun Jo,

    1. School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea
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  • Sung Sik Choe,

    1. School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea
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  • Kyung Cheul Shin,

    1. School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea
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  • Hagoon Jang,

    1. School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea
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  • Jae Ho Lee,

    1. School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea
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  • Je Kyung Seong,

    1. Department of Anatomy and Cell Biology, College of Veterinary Medicine and Research Institute for Veterinary Science, University of Ulsan, Ulsan, Korea
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  • Sung Hoon Back,

    1. School of Biological Sciences, World Class University, University of Ulsan, Ulsan, Korea
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  • Jae Bum Kim

    Corresponding author
    1. School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea
    2. Department of Biophysics and Chemical Biology, Seoul National University, Seoul, Korea
    • School of Biological Sciences, Institute of Molecular Biology & Genetics, Center for Adipose Tissue Remodeling, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, Korea===

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    • fax: (82)-2-878-5852


  • Potential conflict of interest: Nothing to report.

  • Supported by the National Creative Research Initiative Program (2012-0001241) and the World Class University Program (R31-10032) funded by the Ministry of Education, Science, and Technology. H. Jo, S. S. Choe, K. C. Shin, H. Jang, and J. H. Lee were supported by the BK21 program, Korea

Abstract

Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinase–activating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stress–dependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stress–dependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein E–deficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding. Conclusion: These data suggest that ER stress–dependent expression of hepatic VLDLR leads to hepatic steatosis by increasing lipoprotein delivery to the liver, which might be a novel mechanism explaining ER stress–induced hepatic steatosis. (HEPATOLOGY 2013;57:1366–1377)

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