Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China.
Mol Cell Endocrinol. 2011 Sep 15;344(1-2):69-80. doi: 10.1016/j.mce.2011.06.028. Epub 2011 Jul 8.
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.
在之前的实验中，我们发现 E3 大鼠和 DA.1U 大鼠对高脂肪饮食诱导的代谢综合征（HFD-MetS）的反应不同。本研究旨在探讨 E3 大鼠对代谢综合征易感性的遗传差异的原因和分子机制与 DA.1U 大鼠相比。首先，对 E3 和 DA.1U 大鼠进行了为期 12 周的 HFD-MetS 模型建立和评估。然后，采用不同方法测定关键胰岛素信号分子、代谢核受体、代谢关键酶和组蛋白去乙酰化酶（Hdacs）的表达。最后，在 CBRH-7919 细胞和 DA.1U 和 E3 大鼠原代肝细胞中分析 Hdac3 过表达和敲低对代谢核受体的影响。我们发现，E3 大鼠易患 HFD-MetS，而 DA.1U 大鼠则对 HFD-MetS 有抵抗力。DA.1U 大鼠肝脏中 LXR-α、β（LXR-α、β）、法尼醇 X 受体（FXR）、过氧化物酶体增殖物激活受体γ（PPAR-γ）和胆固醇 7α-羟化酶（CYP7A1）的表达明显增加，而 E3 大鼠肝脏中这些基因的表达显著减少。HFD 处理后，E3 和 DA.1U 大鼠肝脏中 Hdac3 的表达均增加，但 DA.IU 大鼠肝脏中 Hdac3 的组成型表达低于 E3 大鼠肝脏。重要的是，Hdac3 的过表达可下调 CBRH-7919 细胞和 DA.IU 大鼠原代肝细胞中 LXR-α、PPAR-γ 和 CYP7A1 的表达。相反，shRNA 敲低 Hdac3 可上调 CBRH-7919 细胞和 E3 大鼠原代肝细胞中 LXR-α、PPAR-γ 和 CYP7A1 的表达。结果表明，肝脏中 Hdac3 的高组成型表达抑制了 PPAR-γ、LXR-α 和 CYP7A1 的表达，导致 E3 大鼠的 HFD-MetS。
