High expression of liver histone deacetylase 3 contributes to high-fat-diet-induced metabolic syndrome by suppressing the PPAR-γ and LXR-α-pathways in E3 rats.

Abstract

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 α,β (LXR-α,β), farnesoid X receptor (FXR), peroxisome proliferator activated receptor γ (PPAR-γ) and cholesterol 7α-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-α, PPAR-γ 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-α, PPAR-γ 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-γ, LXR-α and CYP7A1 in liver contributes to HFD-MetS in E3 rats.

• Authors: Dongmin Li, Xuan Wang, Wuchao Ren, Juan Ren, Xi Lan, Feimiao Wang, Hongmin Li, Fujun Zhang, Yan Han, Tianbao Song, Rikard Holmdahl, Shemin Lu
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 344 Issue 1-2 Pg. 69-80 (Sep 15 2011) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 21763752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Glucose Transporter Type 2
• Glucose Transporter Type 4
• Lipids
• Liver X Receptors
• Nr1h3 protein, rat
• Orphan Nuclear Receptors
• PPAR gamma
• Retinoid X Receptors
• Slc2a2 protein, rat
• Slc2a4 protein, rat
• CYP7A1 protein, rat
• Cholesterol 7-alpha-Hydroxylase
• Receptor, Insulin
• Histone Deacetylases
• histone deacetylase 3

Topics

• Animals
• Cholesterol 7-alpha-Hydroxylase (metabolism)
• Diet, High-Fat (adverse effects)
• Female
• Gene Expression Profiling
• Glucose Transporter Type 2 (genetics, metabolism)
• Glucose Transporter Type 4 (genetics, metabolism)
• Histone Deacetylases (genetics, metabolism)
• Lipids (blood)
• Liver (enzymology, metabolism, pathology)
• Liver X Receptors
• Male
• Metabolic Syndrome (enzymology, etiology)
• Organ Size
• Orphan Nuclear Receptors (metabolism)
• PPAR gamma (metabolism)
• Rats
• Receptor, Insulin (genetics, metabolism)
• Retinoid X Receptors (genetics, metabolism)
• Signal Transduction
• Transcription, Genetic