Transcription coactivator mediator subunit MED1 Is required for the development of fatty liver in the mouse

Authors

  • Liang Bai,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
    2. Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China
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  • Yuzhi Jia,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Navin Viswakarma,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Jiansheng Huang,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Aurore Vluggens,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Nathan E. Wolins,

    1. Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO
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  • Nadereh Jafari,

    1. Genomics Core Facility Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • M. Sambasiva Rao,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Jayme Borensztajn,

    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Gongshe Yang,

    1. Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China
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  • Janardan K. Reddy

    Corresponding author
    1. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
    • Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611
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    • Supported in part by the National Institutes of Health (grants GM23750 and DK083163 to J.K.R; Clinical Nutrition Research Unit grant DK56351 to N.E.W); China Scholarship Council (to L.B.).

    • fax: 312-503-8241


  • Potential conflict of interest: Nothing to report.

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, when overexpressed in liver stimulates the induction of adipocyte-specific and lipogenesis-related genes and causes hepatic steatosis. We report here that Mediator 1 (MED1; also known as PBP or TRAP220), a key subunit of the Mediator complex, is required for high-fat diet–induced hepatic steatosis as well as PPARγ-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPARγ and other transcriptional activators. Liver-specific MED1 knockout (MED1ΔLiv) mice, when fed a high-fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1ΔLiv mice injected with adenovirus-PPARγ (Ad/PPARγ) by tail vein also did not develop fatty liver, whereas mice with MED1 (MED1fl/fl) fed a high-fat diet or injected with Ad/PPARγ developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPARγ–injected mouse livers showed impaired induction in MED1ΔLiv mouse liver of adipogenic markers, such as aP2, adipsin, adiponectin, and lipid droplet-associated genes, including caveolin-1, CideA, S3-12, and others. These adipocyte-specific and lipogenesis-related genes are strongly induced in MED1fl/fl mouse liver in response to Ad/PPARγ. Re-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1ΔLiv mouse liver restored PPARγ-stimulated hepatic adipogenic response. These studies also demonstrate that disruption of genes encoding other coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect on hepatic adipogenesis induced by PPARγ overexpression. Conclusion: We conclude that transcription coactivator MED1 is required for high-fat diet–induced and PPARγ-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;)

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