Prostaglandin E receptor subtype 4 and repressor activator protein 1 : independent multifaceted metabolic players

Abstract

Background and objectives: Inflammatory responses interact with metabolic regulation at various levels. These interactions and the resulting dysfunction(s) can lead to a syndrome of chronic metabolic disease, including dyslipidemia, insulin resistance, diabetes and atherosclerosis. The first two studies of the thesis focuses on whole-body energy and lipid homeostasis. Previous experimental studies illustrated that activation of prostaglandin E2 receptor subtype 4 (EP4) may serve as a therapeutic target to combat inflammatory diseases. However, the metabolic role of this prostanoid receptor remains poorly understood. Hence, the objective of Study I and Study II was to investigate the role of EP4 in the regulation of whole-body metabolism and triglyceride regulation, respectively, during the development of diet-induced obesity in vivo. The third study of the thesis focuses on inflammation. Previous experimental studies demonstrated that, repressor activator protein 1 (Rap1) not only regulates metabolism in the liver of mice, but also promotes inflammatory responses by enhancing nuclear factor kappa B (NFκB) activity in carcinoma cell lines. The objective of Study III was to investigate whether or not Rap1-induced inflammation occurs in macrophages, endothelial cells and or vascular smooth muscle and whether or not this protein contribute to the development of atherosclerosis.

Key findings: 1. Deficiency of EP4 in mice exhibit a higher inflammatory state, to judge from the increased plasma level of serum amyloid A, but develop a reduced body mass compared to wild type controls, especially when they are placed on a highfat diet. Such reduction in body mass is not due to reduced food intake, fat malabsorptionor enhanced energy expenditure, but partly stems from lipid dysregulation, including hypertriglyceridemia and hypercholesterolemia. 2. In high fat diet-fed 〖EP4〗^(-/- ) mice, there is reduced hepatic fatty acid oxidation and lipid synthesis; defects in de novo lipogenesis may override the changes in hepatic fatty acid oxidation, leading to less fat accumulation in high fat diet-fed EP4-/- mice. 3. In high fat diet-fed 〖EP4〗^(-/- )mice, the hypertriglyceridemia phenotype results from a reduced lipoprotein lipase activity, but not from increased intestinal secretion of chylomicron triglycerides or from augmented hepatic production of very low density lipoprotein (VLDL) triglycerides.

4. Rap1 resides in the cytoplasm of macrophages, endothelial and smooth muscle cells, however Rap1 onlyenhances the production of NFκB-mediated pro-inflammatory cytokinesin macrophages through augmenting the phosphorylation of inhibitor of kappa b α(IκBα)and p65. 5. Rap1 is localized in macrophage-rich areas in human atherosclerotic plaques and the presence of Rap1 is positively correlated to the advancement of the disease process. Thus, Rap1 within macrophages may promote the inflammatory process and aggravate the development and progression of human atherosclerosis.

Conclusions: These findings support the fundamental role of EP4 andRap1 in energy homeostasis and inflammation, respectively. The better understanding of the pathogenic mechanisms involving the function or dysfunction of these two independent metabolic players, may yield novel strategies to treat or prevent metabolic and inflammatory disorders.