Cited by 272Histone Deacetylase Inhibitors ResearchPeroxisome Proliferator-Activated ReceptorsCancer, Lipids, and Metabolism

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

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Knutson, Sarah K, Chyla, Brenda J, Amann, Joseph M, Bhaskara, Srividya, Huppert, Stacey S, Hiebert, Scott W·2008·The EMBO Journal

Abstract

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 Ppar gamma2, and treatment of these mice with a Ppar gamma 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.

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Crossref · 10.1038/emboj.2008.51

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  • Mice with a liver-specific deletion of Hdac3 display increased expression of de novo lipogenesis enzymes due to a constitutively active transcriptional environment, resulting in fatty liver disease and elevated serum cholesterol.

    “Mice with a liver-specific deletion of Hdac3 display an increased expression of de novo lipogenesis enzymes due to a constitutively active transcriptional environment, resulting in fatty liver disease and elevated serum cholesterol [178,179].”
  • Sqle is a target of HDAC3, and its transcription increases approximately 170-fold in response to Hdac3 liver deletion.

    “In support of this, Sqle, the suppressor of RTT-like phenotypes in mice, is a target of HDAC3, and its transcription increases approximately 170-fold in response to Hdac3 liver deletion [156,178].”
  • Promoter regions of lipid/cholesterol homeostasis genes, including Sqle, appear to be targets of HDAC3 in the liver.

    “Interestingly, the promoter regions of lipid/cholesterol homeostasis genes, including Sqle, appear to be targets of HDAC3 in the liver55.”
  • FLD in 129.Mecp2tm1.1Bird mice is similar to that in a liver-specific knockout of HDAC3.

    “FLD in 129.Mecp2tm1.1Bird mice is similar to that in a liver-specific knockout of HDAC355,56.”

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Authors
Knutson, S. K., Chyla, B. J., Amann, J. M., Bhaskara, S., Huppert, S. S., & Hiebert, S. W.
Affiliations
Vanderbilt University (US)
Corresponding author
Hiebert, Scott W
Venue
The EMBO Journal
Published
2008-03-20
Volume
27
Issue
7
Pages
1017-1028
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
OpenAlex
W2149370967
Cited by
271
References
69
Citations by year
2026: 3 · 2025: 10 · 2024: 13 · 2023: 20 · 2022: 7 · 2021: 11 · 2020: 18 · 2019: 14 · 2018: 12 · 2017: 16 · 2016: 20 · 2015: 17 · 2014: 17 · 2013: 23 · 2012: 18
FWCI
7.14
Type
journal article
Language
en
Open access
Locations
  • The EMBO Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Leukemia and Lymphoma Society
  • Vanderbilt University (CA68485)
  • Vanderbilt-Ingram Cancer Center (CA68485)
  • National Institutes of Health (CA68485, CA009385)
  • Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
  • National Cancer Institute (CA68485, R01CA077274, R01CA064140, T32CA009385, T32CA009582, P30CA068485, R01 CA64140, R01-CA77274)
  • National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK58404, P30DK058404)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
HDAC3, liver-specific gene deletion, hepatomegaly, hepatocyte hypertrophy, lipid and carbohydrate metabolism, nuclear receptors, transcriptional repression, PPARγ2, PPARγ antagonist, mTOR signaling, rapamycin, hepatic lipid accumulation, metabolic homeostasis
MeSH terms
Histone Deacetylase 3, Acetylation, Animals, Animals, Newborn, Cholesterol, Enzyme Activation, Enzyme Inhibitors, Gene Expression Regulation, Histone Deacetylases, Homeostasis, Hypertrophy, Hypoglycemia, Insulin, Liver, Organ Specificity, Protein Kinases, Gene Deletion, Integrases, Hepatocytes, PPAR gamma, Lipid Metabolism, Mice, Gene Regulatory Networks, TOR Serine-Threonine Kinases

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