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J Mol Endocrinol. 2014 Oct;53(2):191-200. doi: 10.1530/JME-14-0066. Epub 2014 Jun 30.

Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation.

Author information

1
Pennington Biomedical Research CenterLouisiana State University System, Baton Rouge, Louisiana 70808, USADepartment of PathologyShanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology and MetabolismThe Third/Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, ChinaDepartment of Medical TestsXinxiang Medical University, Xinxiang, China.
2
Pennington Biomedical Research CenterLouisiana State University System, Baton Rouge, Louisiana 70808, USADepartment of PathologyShanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology and MetabolismThe Third/Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, ChinaDepartment of Medical TestsXinxiang Medical University, Xinxiang, China Pennington Biomedical Research CenterLouisiana State University System, Baton Rouge, Louisiana 70808, USADepartment of PathologyShanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology and MetabolismThe Third/Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, ChinaDepartment of Medical TestsXinxiang Medical University, Xinxiang, China.
3
Pennington Biomedical Research CenterLouisiana State University System, Baton Rouge, Louisiana 70808, USADepartment of PathologyShanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology and MetabolismThe Third/Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, ChinaDepartment of Medical TestsXinxiang Medical University, Xinxiang, China Pennington Biomedical Research CenterLouisiana State University System, Baton Rouge, Louisiana 70808, USADepartment of PathologyShanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology and MetabolismThe Third/Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, ChinaDepartment of Medical TestsXinxiang Medical University, Xinxiang, China gaoz@pbrc.edu.

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation was required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for the improvement of insulin sensitivity.

KEYWORDS:

HDAC inhibitors; PPARγ; acetylation; adipocytes; adipogenesis; histone deacetylase; insulin sensitivity; metabolic syndrome; posttranslational modifications; type 2 diabetes

PMID:
24982244
PMCID:
PMC4391273
DOI:
10.1530/JME-14-0066
[Indexed for MEDLINE]
Free PMC Article

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