肝脏异维甲酸受体α调控脂代谢通路的基因组靶点分析

Genome-wide analysis of retinoid X receptor α in the lipid metabolism of mouse livers

目的探讨肝脏异维甲酸受体α(RXRα)的基因组靶点特征及其下游通路与脂代谢的关系。方法将6只小鼠随机分为观察组和对照组各3只,分别给予维甲酸150 mg/(kg·d)和等量生理盐水灌胃,共7 d,测定血脂,并用染色体免疫沉淀测序和定量PCR比较RXRα靶基因谱和基因表达差异。结果观察组血清胆固醇和三酰甘油浓度较对照组显著降低(P<0.05),肝脏RXRα的基因组靶点和靶基因数均较对照组增加,以转录起始区靶点增幅最大(约58%)。RXRα的下游通路包括氧化还原、脂肪酸代谢和脂质转运等。观察组脂代谢相关靶基因中约48%(11/23)显著下调,22%(5/23)上调。结论肝脏RXRα及其下游通路是介导维甲酸调控脂代谢通路的重要因子。

Objective To characterize the genome targets of hepatic retinoid X receptor a（RXRca as well as the correlation between its downstream pathways and lipid metabolism. Methods Six mice were divided into treatment group and control group （n = 3 ）, which were treated by retinoic acid 150 rag/（ kg·d） or equal amounts of saline solution for 7 days, respectively. Serum lipid was detected. Hepatic DNA fractions bound by RXRa were immunoprecipitated and sequenced. The distribution of RXRa bindings was characterized. Real - time PCR was used to evaluate the expression of RXRa target genes. Results Serum cholesterol and triglyceride were reduced significantly in treatment group compared to control group（P 〈 0. 05 ）. RXRa bindings and target genes in treatment group were increased compared to control group, among which the overlapped transcriptional start site were increased the most by 58%. Genes implicated in oxidation re- duction, lipid metabolism and lipid transportation were targeted by RXRa. Among the genes associated with lipid metabo- lism in treatment group, 48% （ 11 out of 23 ） were down - regulated whereas 22% （ 5 out of 23 ） were up - regulated sig- nificantly. Conclusion RXRa binds extensively to the mouse liver genome. It regulates the hepatic lipid metabolism at the transcriptional level.