Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 344, Issue 1-2, Pages 69-80Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2011.06.028
Keywords
E3 rat; DA.1U rat; Metabolic syndrome; Histone deacetylase 3; Liver X receptor alpha; Peroxisome proliferator activated receptor gamma
Categories
Funding
- National Natural Science Foundation of China [30400249, 30571725, 30630058]
- Shaanxi Province International Cooperational Foundation of China [2007-kw-06]
- Shaanxi Province Natural Science Foundation of China [2004C256, 2009JM4024, 2010K16-04]
- Fundamental Research Funds for the Central Universities [2009, xjj20100031]
- Swedish Science Research Council
- EU
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In the previous experiment, we found that there was a different response between E3 rats and DA.1U rats to high-fat-diet-induced metabolic syndrome (HFD-MetS). The aim of this study was to explore the cause and molecular mechanism of the genetic difference in susceptibility to metabolic syndrome in E3 rats as compared with DA.1U rats. Firstly, a 12-week HFD-MetS model in E3 and DA.1U rats was carried out and assessed. Then, the expression of key insulin signaling molecules, metabolic nuclear receptors, metabolic key enzymes and histone deacetylases (Hdacs) was determined by different methods. Finally, the effects of overexpression and disruption of Hdac3 on metabolic nuclear receptors were analyzed in CBRH-7919 cells and primarily-hepatic cells from DA.1U and E3 rats. We found that E3 rats were susceptible, while DA.1U rats were resisted to HFD-MetS. The expression of liver X receptor alpha,beta (LXR-alpha,beta), farnesoid X receptor (FXR), peroxisome proliferator activated receptor gamma (PPAR-gamma) and cholesterol 7 alpha-hydroxylase (CYP7A1) increased markedly in DA.1U rat liver, whereas they decreased significantly in E3 rats. The expression of Hdac3 increased by HFD treatment in both E3 and DA.1U rat livers, but the constitutive Hdac3 expression was lower in DA.IU rat liver than in E3 rat liver. Importantly, overexpression of Hdac3 could downregulate the expression of LXR-alpha, PPAR-gamma and CYP7A1 in both CBRH-7919 cells and primarily cultured hepatic cells from DA.IU rats. On the contrary, disruption of Hdac3 by shRNA upregulated the expression of LXR-alpha, PPAR-gamma and CYP7A1 in both CBRH-7919 cells and primarily cultured hepatic cells from E3 rats. The results suggested that a high constitutive expression of Hdac3 inhibiting the expression of PPAR-gamma, LXR-alpha and CYP7A1 in liver contributes to HFD-MetS in E3 rats. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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