E4orf1, A novel adenovirus derived protein to improve diabetes and to reduce liver fat



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The prevalence of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver diseases are rising along with that of obesity. Insulin resistance resulting from impaired insulin signaling is a key factor that interlinks T2DM, hepatic steatosis, and obesity. Hepatic steatosis warrants early intervention, as it can advance to more serious liver conditions, including NAFLD, non-alcoholic steatohepatitis (NASH), cirrhosis, or cancer. In early stages of these diseases, insulin resistance leads to hyperinsulinemia. Insulin promotes hepatic lipogenesis. Hence, reducing hyperinsulinemia may help in treating hepatic steatosis. Considering the close association between T2D and hepatic steatosis, various anti-diabetic drugs have been tested, but they show a modest effect on the reduction of hepatic steatosis. Many of the available ant-diabetic drugs may lead to hypoglycemia. So, a drug that improves diabetes, does not cause hypoglycemia, and ameliorate hepatic steatosis would be highly desirable. E4orf1 is an adenovirus-derived anti-diabetic protein that promotes glucose clearance independent of insulin, lowers insulin amount required for glucose disposal, and reduces hepatic steatosis. In the current stud we evaluated the mechanism for E4orf1-induced reduction in hepatic steatosis and tested if E4orf1 will induce hypoglycemia as an anti-diabetic agent. C57Bl/6J mice that transgenically express E4orf1 in adipose tissue and wild type (WT) mice received a chow diet for 6 weeks, followed by a high fat (HF, 60% kcal from fat) diet for additional 10-weeks. Body composition, blood glucose and serum levels upon glucose load were measured at 0, 6, 7, and 16th weeks. Serum free fatty acid, triglyceride (TG), and hepatic TG were measured at the end of the study. We compared histology and the mRNA/protein markers of hepatic and adipose tissue lipid metabolism between the two groups of mice. E4orf1 expression in mice protected against weight and % body fat gain on chow or HF diet. On chow diet, both groups remained normoglycemic, but E4orf1 expression significantly reduced the insulin response to glucose load compared to WT mice. As anticipated, glycemic control in WT deteriorated on the HF diet. Whereas E4orf1 expression significantly enhanced glycemic control and lowered insulin response to glucose load on HF diet. At study termination, E4orf1 expressing mice had significantly lower hepatic triglycerides, and serum free fatty acids compared to WT mice. 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, with no alteration in TG synthesis. mRNA and protein markers in adipose tissue 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 reduced hepatic steatosis by altering hepatic lipid metabolism, including lipogenesis. This study underscores the possibility of indirectly impacting hepatic steatosis by manipulating adipose tissue metabolism.



Diabetes, NAFLD