Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA.
Nutr Diabetes. 2020 Apr 14;10(1):11. doi: 10.1038/s41387-020-0114-9.
Obesity and type 2 diabetes (T2D) are closely associated with hepatic steatosis (HS), which if untreated can advance to serious liver conditions. Since insulin promotes hepatic lipogenesis, reducing hyperinsulinemia may help in treating HS. E4orf1 is an adenovirus-derived protein that improves glucose clearance independent of insulin, lowers insulin amount required for glucose disposal, and reduces HS. As a next step, we evaluated the mechanism for E4orf1-induced reduction in HS and tested that E4orf1 does not induce hypoglycemia, an important attribute for its application as a potential anti-diabetic agent.
C57Bl/6J mice that transgenically express E4orf1 in adipose tissue (E4orf-Tg) and wild-type (WT) mice received a chow diet for 6 weeks, followed by a high-fat (HF) diet for additional 10 weeks. Body composition, blood glucose, and serum insulin levels upon glucose load were measured at 0, 6, 7, and 16 weeks. Serum free fatty acid (FFA), triglyceride (TG), and hepatic TG were measured at study termination. We compared histology and the mRNA/protein markers of hepatic and adipose tissue lipid metabolism between the two groups of mice.
On chow diet, both groups remained normoglycemic, but E4orf1 expression reduced insulin response. On HF diet, glycemic control in WT deteriorated, whereas E4orf1 significantly enhanced glycemic control, lowered insulin response, reduced hepatic triglycerides, and serum FFA. Overall, a comparison of hepatic mRNA and/or protein expression suggested that E4orf1 expression significantly decreased de novo lipogenesis (DNL) and intracellular lipid transport and increased fat oxidation and TG export. Adipose tissue mRNA and protein markers suggested that E4orf1 expression lowered DNL and increased lipolysis.
Considering that E4orf1 is not secreted in circulation, we postulate that reduced endogenous insulin in E4orf1 mice indirectly contributes to reduce HS by altering hepatic lipid metabolism, including lipogenesis. This study underscores the possibility of indirectly impacting HS by manipulating adipose tissue metabolism.
肥胖和 2 型糖尿病（T2D）与肝脂肪变性（HS）密切相关，如果不加以治疗，HS 可能会发展为严重的肝脏疾病。由于胰岛素促进肝内脂肪生成，降低高胰岛素血症可能有助于治疗 HS。E4orf1 是一种源自腺病毒的蛋白，可独立于胰岛素促进葡萄糖清除，降低葡萄糖处置所需的胰岛素量，并减少 HS。作为下一步，我们评估了 E4orf1 诱导 HS 减少的机制，并测试了 E4orf1 不会引起低血糖，这是其作为潜在抗糖尿病药物应用的一个重要属性。
脂肪组织中转基因表达 E4orf1 的 C57Bl/6J 小鼠（E4orf-Tg）和野生型（WT）小鼠接受了 6 周的标准饮食，然后再接受了 10 周的高脂肪（HF）饮食。在 0、6、7 和 16 周时测量了体重组成、血糖和葡萄糖负荷后的血清胰岛素水平。在研究结束时测量了血清游离脂肪酸（FFA）、甘油三酯（TG）和肝 TG。我们比较了两组小鼠的肝组织学和肝脂肪组织脂质代谢的 mRNA/蛋白标志物。
在标准饮食下，两组均保持血糖正常，但 E4orf1 的表达降低了胰岛素的反应。在 HF 饮食下，WT 组的血糖控制恶化，而 E4orf1 则显著增强了血糖控制，降低了胰岛素反应，减少了肝内 TG 和血清 FFA。总的来说，肝 mRNA 和/或蛋白表达的比较表明，E4orf1 的表达显著降低了从头脂肪生成（DNL）和细胞内脂质转运，增加了脂肪氧化和 TG 输出。脂肪组织 mRNA 和蛋白标志物表明，E4orf1 的表达降低了 DNL 并增加了脂肪分解。
考虑到 E4orf1 不会在循环中分泌，我们推测 E4orf1 小鼠中内源性胰岛素的减少通过改变肝脏脂质代谢，包括脂肪生成，间接导致 HS 减少。这项研究强调了通过操纵脂肪组织代谢间接影响 HS 的可能性。
