内质网应激通过不依赖脂质从头合成的通路诱导非酒精性脂肪肝病

Endoplasmic Reticulum Stress Triggers Non-Alcoholic Fatty Liver Disease Independent of de novo Lipogenesis

内质网应激对代谢状态失衡具有重要影响。近年来研究人员发现内质网应激可以诱导小鼠非酒精性脂肪肝病(NAFLD)的发生发展。但是内质网应激引发肝脏脂肪堆积的机制尚不完全清楚。二脂酰甘油酰基转移酶(DGAT1)是催化甘油三酯合成的关键酶之一,对肝脏脂质合成具有重要意义。在此前的研究中,尚未有人报道过DGAT1在内质网应激诱导NAFLD中的作用。在本研究中,我们通过给小鼠腹腔注射衣霉素,成功诱导了小鼠肝脏内质网应激,发现衣霉素处理的小鼠肝脏有更高的甘油三脂含量并出现较为明显的脂滴堆积。然而,转录水平的检测结果显示该应激并没有上调脂质从头合成关键基因在肝脏中的表达,反而是下调了这些基因的表达。进一步分析发现内质网应激导致小鼠肝脏游离脂肪酸含量显著升高,同时引起肝脏DGAT1表达上调,但并不影响DGAT2的表达。综上,我们的结果表明衣霉素诱导的内质网应激并非通过引发肝脏脂质的从头合成导致肝脏脂肪堆积,而是通过上调肝脏脂肪酸含量以及提高DGAT1的表达,从而促进甘油三酯的合成,导致肝脏脂滴堆积。

Endoplasmic Reticulum(ER)stress plays important roles on metabolic dysfunction.In recent years,endoplasmic reticulum stress has been found to induce non-alcoholic fatty liver disease(NAFLD)in mice.However,the underlying mechanism of ER stress-triggering liver fat accumulation is not fully understood.Diacylglycerol O-acyltransferase 1(DGAT1)is one of the key enzymes catalyzing the synthesis of triglycerides,which is critical for lipid synthesis in liver.The role of DGAT1 in ER stress-induced NAFLD is currently unclear.In this study,we treated mice with tunicamycin which can cause ER stress and found that ER stress caused significant fat accumulation in liver.Surprisingly,tunicamycin treatment did not upregulate de novo lipogenesis related genes.Further studies showed that the expression of DGAT1 was significantly increased upon tunicamycin treatment.Moreover,the level of free fatty acid in liver was also increased by ER stress.Thus,our study shows that expression of DGAT1 and level of free fatty acid in liver were both up-regulated by ER stress,which may cause the increasing level of triglyceride and hepatic steatosis.