Zhang Quan, Li Yan, Liang Tingting, Lu Xuemian, Zhang Chi, Liu Xingkai, Jiang Xin, Martin Robert C, Cheng Mingliang, Cai Lu
1. Department of Infectious Diseases, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China, 550004 ; 4. Kosair Children's Hospital Research Institute, the Department of Pediatrics of the University of Louisville, Louisville, KY 40202, USA.
2. Department of Surgery, School of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Int J Biol Sci. 2015 Apr 2;11(5):559-68. doi: 10.7150/ijbs.10690. eCollection 2015.
Diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are often identified in patients simultaneously. Recent evidence suggests that endoplasmic reticulum (ER) stress and autophagy dysfunction play an important role in hepatocytes injury and hepatic lipid metabolism, however the mechanistic interaction between diabetes and NAFLD is largely unknown. In this study, we used a diabetic mouse model to study the interplay between ER stress and autophagy during the pathogenic transformation of NAFLD. The coexist of inflammatory hepatic injury and hepatic accumulation of triglycerides (TGs) stored in lipid droplets indicated development of steatohepatitis in the diabetic mice. The alterations of components for ER stress signaling including ATF6, GRP78, CHOP and caspase12 indicated increased ER stress in liver tissues in early stage but blunted in the later stage during the development of diabetes. Likewise, autophagy functioned well in the early stage but suppressed in the later stage. The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition. We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.
糖尿病和非酒精性脂肪性肝病（NAFLD）在患者中常常同时被发现。最近的证据表明，内质网（ER）应激和自噬功能障碍在肝细胞损伤和肝脏脂质代谢中起重要作用，然而糖尿病与NAFLD之间的机制性相互作用在很大程度上尚不清楚。在本研究中，我们使用糖尿病小鼠模型来研究NAFLD致病转化过程中ER应激与自噬之间的相互作用。炎症性肝损伤与储存在脂滴中的甘油三酯（TGs）肝脏蓄积并存，表明糖尿病小鼠发生了脂肪性肝炎。ER应激信号通路成分包括ATF6、GRP78、CHOP和caspase12的改变表明，在糖尿病发展过程中，肝脏组织早期ER应激增加，但后期减弱。同样，自噬在早期功能良好，但在后期受到抑制。未折叠蛋白反应的失活和自噬的抑制与脂肪性肝炎的发展呈正相关，这与糖尿病状态下受损肝组织中的代谢异常有关。我们得出结论，ER应激的适应和自噬的受损在加剧脂质代谢紊乱从而导致糖尿病性脂肪性肝炎方面起重要作用。
