Laboratory Animal Research Center, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Institute of Comparative Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China; School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Laboratory Animal Research Center, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Institute of Comparative Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Life Sci. 2020 Jun 1;250:117514. doi: 10.1016/j.lfs.2020.117514. Epub 2020 Mar 5.
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.
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.
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.
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.
猪越来越多地被用作人类代谢疾病模型；然而，关于品种相关遗传背景差异的研究还不够充分。本研究旨在探讨两种小型猪品种对高脂肪和高胆固醇（HFC）饮食诱导的非酒精性脂肪性肝病（NAFLD）的代谢反应差异，并探讨相关的分子机制。
雄性五指山猪（WZSP）和藏猪（TP）随机分为标准饮食组或 HFC 饮食组，分别喂养 24 周。测定体重、血清脂质、胆汁酸、胰岛素抵抗、肝功能、肝组织学和肝脂质沉积。采用 RNA-Seq 检测肝基因表达谱。Western blot、免疫组化和 qRT-PCR 检测脂质和葡萄糖代谢相关基因表达。
HFC 饮食导致两种猪肥胖、高血压、严重高胆固醇血症、肝损伤、肝细胞脂肪变性和炎症增加，血清胰岛素水平显著升高。该饮食导致 WZSP 血清和肝胆固醇水平升高，TP 空腹血糖升高。转录组分析表明，控制肝胆固醇代谢和炎症反应的基因受到一致调控；HFC 饮食分别在 WZSP 和 TP 中特异性调控脂质代谢和胰岛素信号相关基因。
本研究表明遗传背景对猪对 HFC 饮食的代谢和肝反应有深远影响。这些结果加深了我们对 HFC 饮食诱导的 NAFLD 分子机制的理解，并为未来选择合适的猪品种进行代谢研究提供了基础。
