Role of Prostaglandin E Receptor Subtype 4 (EP4) in the Regulation of Triglyceride Metabolism

Abstract

Objectives: Hypertriglyceridemia is strongly associated with future risk of insulin resistance, diabetes and cardiovascular disease. Interestingly, it has been recently demonstrated that mice lacking cyclic AMP-responsive element-binding protein H (CREB-H) showed higher plasma triglyceride concentrations compared to wild-type mice. As an upstream stimulating factor of CREB-H, prostaglandin E receptor subtype 4 (EP4) may participate in the regulation of triglyceride metabolism. Thus, we tested whether or not deletion of EP4 influences triglyceride metabolism, and if so, to explore the underlying mechanisms. Methods: EP4 wild-type and knockout mice were put on a high-fat diet (HFD) for thirty weeks and changes in plasma triglycerides were monitored. The impact of EP4 deletion on the ability to synthesize hepatic very low density lipoprotein (VLDL)-triglyceride (TG) and intestinal chylomicron (CM)-TG, as well as the ability to clear TG during HFD was examined. Lipoprotein lipase (LPL) activity and mRNA expression of LPL and CD36 in brown adipose tissue (BAT) were determined by fluorometric assay kit and quantitative polymerase chain reaction (Q-PCR), respectively. Results: After thirty weeks of high-fat diet, EP4 knockout mice had a higher plasma TG level than wild-type mice. The deletion of EP4 did not influence hepatic VLDL-TG production or intestinal CM-TG synthesis but impaired TG clearance rate. EP4 knockout mice had a decreased mRNA expression and activity of LPL in their BAT, suggesting impaired hydrolysis and uptake of triglycerides in this tissue. Moreover, EP4 knockout mice had a reduced expression of CD36 in BAT, which may indicate that the uptake of fatty acids is impaired. Conclusions: Deletion of EP4 in high-fat fed mice resulted in hypertriglyceridemia. The hypertriglyceridemia that accompanies EP4 deficiency is the result of impaired TG clearance, attributed to reduced mRNA expression of LPL and CD36, and impaired LPL activity in BAT. The results indicate that EP4 plays a critical role in systemic lipid homeostasis.