National Institute of Immunology, New Delhi, India.
Institute of Liver and Biliary Sciences, New Delhi, India.
Cell Biochem Funct. 2021 Mar;39(2):296-307. doi: 10.1002/cbf.3579. Epub 2020 Aug 6.
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein involved in redox signalling and programmed cell death. The role of AIF has been well recognized in diabetes and obesity. However, the aspect of AIF deficiency in the development of hepatic steatosis and liver injury is unknown. Therefore, in the current study, Harlequin (Hq mutant) mouse with markedly reduced content of AIF was investigated to explore the role of AIF on the initiation of liver injury. The wild type (WT) developed physiological and pathological features of non-alcoholic fatty liver disease (NAFLD) that were not seen in the Hq mice with AIF deficiency, when fed on high fat high fructose (HFHF) diet. Following bile duct ligation (BDL), the liver associated pathological changes were less conspicuous in Hq mice as compared to WT mice. The expression of AIF protein and apoptosis was markedly lesser as compared to their respective control in Hq mice on HFHF diet. Furthermore, the genes involved in fatty acid metabolism were also altered in the group of treated Hq mice. In conclusion, Hq mice failed to develop diet induced hepatic steatosis, suggestive of a role of AIF mediated pathway in the initiation and progression of liver inflammation. Thus, partial loss of AIF appears to be hepatoprotective. SIGNIFICANCE OF THE STUDY: AIF deficiency has multiple roles in altered pathology processes and cellular metabolism, thereby compromising the cellular homeostasis. Considering the molecular functions of AIF in other organ pathology little is known about its role in diet induced liver injury. Hence, the aim of the current study was to investigate the role of AIF deficiency in liver injury and diseases with focus on NAFLD. The study will help to deliniate the mechanisms of NAFLD using Harliquin Mice.
凋亡诱导因子（AIF）是一种参与氧化还原信号和程序性细胞死亡的线粒体黄素蛋白。AIF 在糖尿病和肥胖症中的作用已得到充分认识。然而，AIF 缺乏在肝脂肪变性和肝损伤发展中的作用尚不清楚。因此，在目前的研究中，研究了 AIF 含量明显降低的 Harlequin（Hq 突变）小鼠，以探讨 AIF 在肝损伤起始中的作用。当喂食高脂肪高果糖（HFHF）饮食时，野生型（WT）小鼠发展出非酒精性脂肪性肝病（NAFLD）的生理和病理特征，而 AIF 缺乏的 Hq 小鼠则没有。在胆管结扎（BDL）后，与 WT 小鼠相比，Hq 小鼠的肝脏相关病理变化不太明显。与 HFHF 饮食的相应对照相比，Hq 小鼠中 AIF 蛋白和凋亡的表达明显减少。此外，在处理后的 Hq 小鼠中，脂肪酸代谢相关基因也发生了改变。总之，Hq 小鼠未能发展出饮食诱导的肝脂肪变性，提示 AIF 介导的途径在肝炎症的发生和进展中起作用。因此，AIF 的部分缺失似乎具有肝保护作用。研究的意义：AIF 缺乏在改变的病理过程和细胞代谢中具有多种作用，从而损害细胞内稳态。考虑到 AIF 在其他器官病理学中的分子功能，关于其在饮食诱导的肝损伤中的作用知之甚少。因此，本研究的目的是研究 AIF 缺乏在肝损伤和疾病中的作用，重点是 NAFLD。该研究将有助于使用 Harliquin 小鼠阐明 NAFLD 的机制。
