Topical Area: Energy and Macronutrient Metabolism
Objectives : Adenovirus-36-derived E4orf1 peptide reduces hepatic fat accumulation, fibrosis, and inflammation in high fat fed mice. This property of E4orf1 could be exploited to prevent or treat broader spectrum of fatty liver diseases. Our previous in vitro study suggested that E4orf1 reduces de novo lipogenesis, and increases complete fatty acid oxidation and lipid export in hepatocytes. To better understand the phenomenon, this ex vivo study examined the genes of hepatic lipid metabolism in mice that transgenically express E4orf1.
We used C57BL/6 mice transgenically expressing E4orf1 in the adipose tissue induced upon doxycycline ingestion (Tg) and wild type C57BL/6 mice (WT) as control. Experiment 1: E4orf1 expression was induced in Tg mice (27 wk old, n=3) by feeding chow-doxycycline diet for 6 weeks, followed by 10 weeks of 60% high-fat (HF) diet with doxycycline. WT mice (n=4) also received the same diet for the period. Experiment 2: 50 wk old Tg mice positive or negative for E4orf1 (Tg+, n=4 and Tg-, n=5, respectively) received HF-doxycycline diets for 20 weeks. At termination, mice were sacrificed and hepatic RNA was extracted. The expression of key genes associated with hepatic lipid metabolism were determined by RT-PCR.
Results : Experiment 1: The activation of E4orf1 significantly downregulated genes involved in lipogenesis (ChREBP and FASn), lipid import (L-FABP, FATP2, FATP5), and lipid export (ApoB). PPARα and HSD11β1 gene expressions were significantly lower suggesting lower lipid accumulation. Experiment 2: Tg+ mice had significantly lower expressions of SREBP1c, the key promoter of lipogenesis, FASn, and ApoB. E4orf1 did not significantly influence the expressions of key genes of lipid oxidation, such as PGC1α, and CPT1 in both experiments.
Similar to our in vitro data with hepatocytes, this in vivo study indicated the effect of E4orf1 on lipogenesis, but not on lipid oxidation. Overall, the results suggest that E4orf1 reduces de novo lipogenesis and lipid import to the liver, which may lead to reduced hepatic lipid accumulation in mice. This reduced hepatic lipogenesis may protect the E4orf1 expressing mice from progression to hepatic inflammation and fibrosis despite the high fat diet.
Funding Sources : None