The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks
Open accessAbstract
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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“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].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [178]
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“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].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [178]
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“Interestingly, the promoter regions of lipid/cholesterol homeostasis genes, including Sqle, appear to be targets of HDAC3 in the liver55.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [55]
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“FLD in 129.Mecp2tm1.1Bird mice is similar to that in a liver-specific knockout of HDAC355,56.”
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Metadata
- 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
- PMC
- PMC2323257
- 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
- bronze
- doi.org
- Licence
- 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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