高脂饮食显著改变了参与小鼠肝脏药物代谢和药代动力学系统的整体基因表达谱。
High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice.
作者信息
He Yuqi, Yang Tao, Du Yimei, Qin Lin, Ma Feifei, Wu Zunping, Ling Hua, Yang Li, Wang Zhengtao, Zhou Qingdi, Ge Guangbo, Lu Yanliu
机构信息
The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China.
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription and the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines , Shanghai University of Traditional Chinese Medicine, Shanghai, China.
出版信息
Nutr Metab (Lond). 2020 May 24;17:37. doi: 10.1186/s12986-020-00456-w. eCollection 2020.
BACKGROUND
High fat diet impact transcription of hepatic genes responsible for drug metabolism and pharmacokinetics. Until now, researches just focused on a couple specific genes without a global profile showing. Age-dependent manner was also not noted well. This study aims to investigate the high fat diet effect on transcriptome of drug metabolism and pharmacokinetic system in mouse livers and show the age-dependent evidence.
METHODS
C57BL/6 male mice were used in this experiment. High fat diet was used to treat mice for 16 and 38 weeks. Serum total cholesterol, low density lipoprotein cholesterol, aspartate transaminase, and alanine transaminaselevels were measured. Meanwhile, Histology, RNA-Seq, RT-PCR analysis and fourteen major hepatic bile acids quantification were performed for the liver tissues. Data was mined at levels of genes, drug metabolism and pharmacokinetic sysem, and genome wide.
RESULTS
Treatment with high fat diet for 38 weeks significantly increased levels of serum lipids as well as aspartate transaminase, and alanine transaminase. Meanwhile, lipid accumulation in livers was observed. At week 38 of the experiment, the profile of 612 genes involved in drug metabolism and pharmacokinetics was significantly changed, indicated by a heatmap visulization and a principal component analysis. In total 210 genes were significantly regulated. Cyp3a11, Cyp4a10, and Cyp4a14 were down-regulated by 10-35 folds, while these three genes also were highly expressed in the liver. High fat diet regulated 11% of genome-wide gene while 30% of genes involved in the hepatic drug metabolism and pharmacokinetic system. Genes, including and , were regulated by high fat diet as an aging-dependent manner. Bile acids homeostasis, in which many genes related to metabolism and transportation were enriched, was also changed by high fat diet with an aging-dependet manner. Expression of genes in drug metabolism and disposition system significantly correlated to serum lipid profiles, and frequently correlated with each other.
CONCLUSIONS
High fat diet changed the global transcription profile of hepatic drug metabolism and pharmacokinetic system with a age-dependent manner.
背景
高脂饮食会影响负责药物代谢和药代动力学的肝脏基因的转录。到目前为止，研究仅聚焦于少数几个特定基因，尚无整体概况展示。年龄依赖性方式也未得到充分关注。本研究旨在探究高脂饮食对小鼠肝脏药物代谢和药代动力学系统转录组的影响，并呈现年龄依赖性证据。
方法
本实验使用C57BL/6雄性小鼠。采用高脂饮食处理小鼠16周和38周。检测血清总胆固醇、低密度脂蛋白胆固醇、天冬氨酸转氨酶和丙氨酸转氨酶水平。同时，对肝脏组织进行组织学、RNA测序、逆转录聚合酶链反应分析以及14种主要肝胆汁酸定量分析。在基因、药物代谢和药代动力学系统以及全基因组水平挖掘数据。
结果
高脂饮食处理38周显著升高了血清脂质以及天冬氨酸转氨酶和丙氨酸转氨酶水平。同时，观察到肝脏中的脂质积累。在实验第38周，参与药物代谢和药代动力学的612个基因的概况发生了显著变化，热图可视化和主成分分析表明了这一点。总共210个基因受到显著调控。Cyp3a11、Cyp4a10和Cyp4a14下调了10至35倍，而这三个基因在肝脏中也高度表达。高脂饮食调节了全基因组11%的基因，而参与肝脏药物代谢和药代动力学系统的基因有30%受到调节。包括[具体基因1]和[具体基因2]在内的基因以年龄依赖性方式受到高脂饮食的调节。胆汁酸稳态也因高脂饮食以年龄依赖性方式发生改变，其中许多与代谢和转运相关的基因富集。药物代谢和处置系统中的基因表达与血清脂质谱显著相关，且经常相互关联。
结论
高脂饮食以年龄依赖性方式改变了肝脏药物代谢和药代动力学系统的整体转录概况。
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