Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c–dependent mechanism in mice

Authors

  • Jing Wu,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
    2. Department of Pathophysiology, Hebei United University, Tangshan, China
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    • These authors equally contributed to this work.

  • Chunjiong Wang,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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    • These authors equally contributed to this work.

  • Shuo Li,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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    • These authors equally contributed to this work.

  • Sha Li,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Wanyi Wang,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Jing Li,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Yujing Chi,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Hang Yang,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Xiaomu Kong,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Yunfeng Zhou,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Chengyan Dong,

    1. Medical Isotopes Research Center, Peking University Health Science Center, Beijing, China
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  • Fan Wang,

    1. Medical Isotopes Research Center, Peking University Health Science Center, Beijing, China
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  • Guoheng Xu,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Jichun Yang,

    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
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  • Jan-Åke Gustafsson,

    1. Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX
    2. Department of BioSciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden
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  • Youfei Guan

    Corresponding author
    1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China
    • Address reprint requests to: Youfei Guan, M.D., Ph.D., Department of Physiology and Pathophysiology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 1000191, ChinaJan-Åke Gustafsson, PhD Center for Nuclear Receptors and Cell Signaling, UniversityofHouston, 3013 Cullen Blv, 77204, Houston,Texas, USA, Tel:(001)832-842-8803, E-mail: jgustafsson@uh.edu. E-mail: youfeiguan@bjmu.edu.cn fax: +86 10-8280-14471;

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Ministry of Science and Technology (2012CB517504/2011ZX09102, to Y.G.; 2009CB941603, to J.Y. and G.X.; 2010CB912503, to Y.G.; and 2011CB707703 and 2013CB733802, to F.W.) and the Natural Science Foundation (30870905/81030003; to Y.G.). This work was also supported by National Natural Science Foundation of China (30900499; to J.W.) and the Specialized Research Fund for the Doctoral Program of Higher Education (20090001120042; to J.W.). J.Å.G. is grateful to the Swedish Research Council and the Robert A. Welch Foundation for support.

Abstract

The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet–fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element–like elements and one sterol regulatory element (SRE)-binding site within a −2,468 ∼+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c–induced Thrsp transcription. Conclusion: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α–mediated, SREBP-1c–dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD. (Hepatology 2013;58:617–628)

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