Mostofinejad Zahra, Akheruzzaman Md, Abu Bakkar Siddik Md, Patkar Presheet, Dhurandhar Nikhil V, Hegde Vijay
Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA.
Department of Nutrition and Environmental Toxicology, University of California, Davis, California, USA.
BMJ Open Diabetes Res Care. 2021 May;9(1). doi: 10.1136/bmjdrc-2020-002096.
Older age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice.
We used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT Profiler PCR array.
Compared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition.
E4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.
老年与高胰岛素血症、2型糖尿病和脂肪肝病的患病率较高有关。这些代谢状况与衰老与线粒体功能障碍和端粒损耗存在双向联系。尽管有效应对这些状况对于影响健康和寿命很重要，但在老年人群中尤其具有挑战性。我们曾报道，源自人类腺病毒Ad36的蛋白质E4orf1可降低高脂饮食（HFD）喂养的年轻小鼠的高胰岛素血症，改善葡萄糖清除，并预防肝脂肪变性。在此，我们测试了E4orf1是否能改善老年小鼠的血糖控制、肝脏脂肪堆积、线粒体完整性，并减少端粒损耗。
我们使用了在脂肪组织中可诱导表达E4orf1的9月龄小鼠以及不表达E4orf1的对照小鼠。小鼠维持60%（千卡）的高脂饮食20周，并在第20周通过腹腔葡萄糖耐量试验测定血糖控制情况。在高脂喂养20周后，处死小鼠并收集肝脏组织，使用基于qRT-PCR的RT Profiler PCR芯片测定衰老基因的表达。
与对照小鼠相比，E4orf1显著改善了血糖控制，减少了肝脏脂肪变性和纤维化。此外，E4orf1维持了线粒体完整性和端粒损耗的标志物。
E4orf1有潜力改善老年小鼠的血糖控制，且即使在长期暴露后这种改善依然存在。E4orf1的表达还维持了线粒体完整性和端粒损耗，从而延缓与年龄相关的疾病。这为E4orf1在改善人类衰老过程中发生的与年龄相关的代谢和细胞变化方面的治疗效用提供了有力证据。
