Differential metabolic and hepatic transcriptome responses of two miniature pig breeds to high dietary cholesterol
Differential metabolic and hepatic transcriptome responses of two miniature pig breeds to high dietary cholesterol
复制标题
两个小型猪品种对高膳食胆固醇的不同代谢和肝脏转录组反应
DOI：
10.1016/j.lfs.2020.117514
复制
发表时间：
2020-06-01
期刊：
影响因子：
6.1
通讯作者：
Chen, Minli
中科院分区：
文献类型：
--
作者：
Cai, Zhaowei;Yu, Chen;Chen, Minli
目的：猪越来越多地被用作人类代谢性疾病的模型，然而，对与品种相关的遗传背景差异的研究还不够充分。本研究旨在研究两个小型猪品种对高脂高胆固醇(HFC)饲料诱导的非酒精性脂肪性肝病(NAFLD)的不同代谢反应，并探讨其分子机制。主要方法：雄性五指山猪(WZSP)和藏猪(TP)随机分别饲喂标准饲料和HFC饲料24周。测定体重、血脂、胆汁酸、胰岛素抵抗、肝功能、肝组织学和肝脂沉积。采用RNA-Seq技术检测肝组织基因表达谱。通过Western印迹、免疫组织化学和qRT-PCR检测脂肪和糖代谢相关基因的表达。主要发现：HFC饲料导致两个品种的猪肥胖、高血压、严重的高胆固醇血症、肝脏损伤、肝细胞脂肪变性和炎症增加，并显著提高血清胰岛素水平。这种饮食导致WZSP的血清和肝脏胆固醇水平较高，TP的空腹血糖水平较高。转录组分析表明，控制肝脏胆固醇代谢和炎症反应的基因在WZSP和TP中是一致调控的；脂肪代谢和胰岛素信号相关基因分别在WZSP和TP中受HFC饲料独有的调控。意义：我们的研究表明，遗传背景深刻地影响了猪对HFC饲料的代谢和肝脏反应。这些结果加深了我们对HFC饮食诱导NAFLD分子机制的认识，为今后选择合适的猪品种进行代谢研究提供了基础。
Aims: Pigs are increasingly used as human metabolic disease models; however, there is insufficient research on breed-related genetic background differences. This study aimed to investigate the differential metabolic responses to high-fat and high-cholesterol (HFC) diet-induced non-alcoholic fatty liver disease (NAFLD) of two miniature pig breeds and explore the molecular mechanisms involved.Main methods: Male Wuzhishan (WZSP) and Tibetan pigs (TP) were randomly fed either a standard or an HFC diet for 24 weeks. Weight, serum lipids, bile acid, insulin resistance, liver function, liver histology, and hepatic lipid deposition were determined. RNA-Seq was used to detect the hepatic gene expression profiles. Western blot, immunohistochemistry, and qRT-PCR were used to detect the lipid and glucose metabolism-related gene expressions.Key findings: The HFC diet caused obesity, hypertension, severe hypercholesterolemia, liver injury, increased hepatocellular steatosis and inflammation, and significantly increased serum insulin levels in both pig breeds. This diet led to higher serum and hepatic cholesterol level concentrations in WZSP and elevated fasting glucose levels in TP. Transcriptome analysis revealed that the genes controlling hepatic cholesterol metabolism and the inflammatory response were consistently regulated; lipid metabolism and insulin signaling related genes were uniquely regulated by the HFC diet in the WZSP and TP, respectively.Significance: Our study demonstrated that the genetic background affects profoundly pigs' metabolic and hepatic responses to an HFC diet. These results deepened our understanding of the molecular mechanisms of HFC diet-induced NAFLD and provided a foundation for selecting the appropriate pig breeds for metabolic studies in the future.