Hepatic transcriptomic analyses revealing the molecular pathogenesis of T2DM associated NAFLD in the ZDF rats

The ZDF rat, with spontaneous homozygous mutation of the leptin receptor gene (fa/fa), is one of the widely used animal model for studying the human type 2 diabetes mellitus (T2DM). Male ZDF rats have the symptoms of obesity and insulin resistance at a young age, accompanying with impaired islet function. However, their hepatic pathogenesis is still unclear. Based on the successive observations and the transcriptomic analyses of the liver tissue at 22 weeks old, we detected the typical clinical indications of T2DM, severe hepatic metabolic remodeling and the inflammatory liver injury in the ZDF rats. The integrin linked kinase signaling, as well as the endoplasmic reticulum stress and its downstream p38 MAPK signaling, seemed to play crucial roles in it. We have proved the ZDF rats could better simulate the pathogenesis of the human T2DM associated nonalcoholic fatty liver disease (NAFLD), and provided targets and reference for future T2DM studies.携带瘦素受体基因（leptin receptor gene）自发纯合突变（fa/fa）的ZDF大鼠（ZDF rat），是目前研究人类2型糖尿病（type 2 diabetes mellitus, T2DM）最常用的动物模型之一。雄性ZDF大鼠在幼年阶段即表现出肥胖与胰岛素抵抗症状，并伴随胰岛功能受损。然而其肝脏发病机制至今尚未明确。本研究通过对22周龄ZDF大鼠的肝脏组织进行连续观察与转录组分析，检测到该模型大鼠呈现典型的T2DM临床指征、严重的肝脏代谢重构及炎症性肝损伤。其中，整合素连接激酶信号通路（integrin linked kinase signaling）、内质网应激（endoplasmic reticulum stress）及其下游的p38丝裂原活化蛋白激酶（p38 MAPK）信号通路可能在该过程中发挥关键调控作用。本研究证实ZDF大鼠可更好地模拟人类T2DM相关性非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）的发病机制，为后续T2DM相关研究提供了潜在靶点与参考依据。