Antidiabetic E4orf1 protein prevents hepatic steatosis and reduces markers of aging-related cellular damage in high fat fed older mice.
Antidiabetic E4orf1 protein prevents hepatic steatosis and reduces markers of aging-related cellular damage in high fat fed older mice.
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DOI：
10.1136/bmjdrc-2020-002096
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发表时间：
2021-05
影响因子：
4.1
通讯作者：
Hegde V
中科院分区：
文献类型：
--
作者：
Mostofinejad Z;Akheruzzaman M;Abu Bakkar Siddik M;Patkar P;Dhurandhar NV;Hegde V
年龄越大，高胰岛素血症、2型糖尿病和脂肪肝的患病率越高。这些代谢状况和衰老与线粒体功能障碍和端粒磨损双向相关。虽然有效地解决这些问题对影响健康和寿命很重要，但在老年人中尤其具有挑战性。我们报道了E4 orf 1，一种来源于人腺病毒Ad 36的蛋白，在暴露于高脂饮食（HFD）的年轻小鼠中降低高胰岛素血症，改善葡萄糖清除，并防止肝脏脂肪变性。在这里，我们测试了E4 orf 1是否会改善老年小鼠的血糖控制，肝脏脂肪积累，线粒体完整性，并减少端粒磨损。我们使用9个月大的小鼠，诱导表达E4 orf 1的脂肪组织和非E4 orf 1表达对照小鼠。小鼠维持60%（kcal）HFD 20周，并在第20周通过腹膜内葡萄糖耐量试验确定血糖控制。在HF喂养20周后，处死小鼠并收集肝组织以使用基于qRT-PCR的RT 2 Profiler PCR阵列测定衰老基因的表达。与对照小鼠相比，E4 orf 1显著改善了血糖控制，减少了肝脂肪变性和纤维化。此外，E4 orf 1保持线粒体完整性和端粒磨损的标志物。E4 orf 1有可能改善老年小鼠的血糖控制，即使在长期暴露后，这种改善也会持续。E4 orf 1的表达也维持线粒体的完整性和端粒的磨损，从而延缓年龄相关疾病。这为E4 orf 1在改善与人类衰老相关的代谢和细胞变化方面的治疗效用提供了强有力的证据。
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 RT2 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.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
14.9
作者：
Bluhm, Alina;Viceconte, Nikenza;Butter, Falk
通讯作者：
Butter, Falk
影响因子：
8.1
作者：
Kusminski CM;Gallardo-Montejano VI;Wang ZV;Hegde V;Bickel PE;Dhurandhar NV;Scherer PE
通讯作者：
Scherer PE
DOI：
10.1042/bj20141018
发表时间：
2015-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Dassanayaka S;Readnower RD;Salabei JK;Long BW;Aird AL;Zheng YT;Muthusamy S;Facundo HT;Hill BG;Jones SP
通讯作者：
Jones SP
影响因子：
13.1
作者：
Mercken, Evi M.;Carboneau, Bethany A.;Krzysik-Walker, Susan M.;de Cabo, Rafael
通讯作者：
de Cabo, Rafael