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  • The EMBO Journal (2008) 27, 1017 - 1028
  • doi:10.1038/emboj.2008.51

Published online: 20 March 2008

Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks

Sarah K Knutson1, Brenda J Chyla1,5, Joseph M Amann1,2, Srividya Bhaskara1, Stacey S Huppert3 and Scott W Hiebert1,4

  1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
  2. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
  3. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
  4. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence to:

Scott W Hiebert, Department of Biochemistry, Vanderbilt University School of Medicine, 512 Preston Research Building, 23rd and Pierce Avenue, Nashville, TN 37232, USA. Tel.: +1 615 936 3582; Fax: +1 615 936 1790; E-mail: scott.hiebert@vanderbilt.edu

5Present address: Abbott Laboratories, Abbott Park, IL, USA

Received 5 February 2008; Accepted 25 February 2008

Histone deacetylase 3 (Hdac3) is an enzymatic component of transcriptional repression complexes recruited by the nuclear hormone receptors. Inactivation of Hdac3 in cancer cell lines triggered apoptosis, and removal of Hdac3 in the germ line of mice caused embryonic lethality. Therefore, we deleted Hdac3 in the postnatal mouse liver. These mice developed hepatomegaly, which was the result of hepatocyte hypertrophy, and these morphological changes coincided with significant imbalances between carbohydrate and lipid metabolism. Loss of Hdac3 triggered changes in gene expression consistent with inactivation of repression mediated by nuclear hormone receptors. Loss of Hdac3 also increased the levels of Ppargamma2, and treatment of these mice with a Ppargamma antagonist partially reversed the lipid accumulation in the liver. In addition, gene expression analysis identified mammalian target of rapamycin signalling as being activated after deletion of Hdac3, and inhibition by rapamycin affected the accumulation of neutral lipids in Hdac3-null livers. Thus, Hdac3 regulates metabolism through multiple signalling pathways in the liver, and deletion of Hdac3 disrupts normal metabolic homeostasis.

  • Keywords:

    • chromatin,
    • Hdac3,
    • histone acetylation,
    • metabolism