|Zingg, Jean-Marc -|
|Hasan, Syeda T. -|
|Cowan, Danica -|
|Ricciarelli, Roberta -|
|Azzi, Angelo -|
|Meydani, Mohsen -|
Submitted to: Journal of Cellular Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 6, 2011
Publication Date: March 1, 2012
Citation: Zingg, J., Hasan, S., Cowan, D., Ricciarelli, R., Azzi, A., Meydani, M. 2012. Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages. Journal of Cellular Biochemistry. 113:833-840. Interpretive Summary: Certain cells in the body known as monocytes and macrophages are important in the development of atherosclerosis, a disease that causes a thickening of the interior walls of blood vessels. These cells are key factors because they cause inflammation and the formation of fatty deposits in the blood vessels. Recent evidence suggests that curcumin, a natural substance found in the spice turmeric, may reduce inflammation and atherosclerosis. We found that curcumin can modify the accumulation of lipids or fatty deposits in monocytes/macrophage cells, a process important in the development of atherosclerosis. In cultures at a cell and molecular level, curcumin increased the function of two specific genes [CD36/FAT and FABP4/aP2], which are involved in the removal of fat from the blood stream. When supplementing a high fat diet of mice with curcumin, we found reduced amounts of fat in the blood and in the macrophages. Additionally, we learned that curcumin changed the activity of a gene known as FOXO3a, which is a regulatory gene. Our results suggest that this gene controls the activity of the two genes mentioned above, but this would require further investigation. The results may indicate a way to prevent age-dependent, increased risk of atherosclerosis. Using a natural substance like curcumin or developing a drug from this substance might prove to be a strategy to protect against damage in the inflammatory cells of the vascular system, which would reduce the development of atherosclerosis.
Technical Abstract: Recent evidence suggests potential benefits from phytochemicals and micronutrients in protecting against oxidative and lipid-mediated damage, but the molecular mechanisms of these actions are still unclear. Here we investigated whether the dietary polyphenol curcumin can modulate the accumulation of lipids in monocytes/macrophages. Curcumin increased the expression of two lipid transport genes, the fatty acids transporter CD36/FAT and the fatty acids binding protein 4 FABP4/aP2, leading to increased lipid levels in THP-1 and RAW264.7 monocytes and macrophages. To investigate the molecular mechanism involved, we assessed the activity of FOXO3a, a transcription factor centrally involved in regulating several stress resistance and lipid transport genes. Curcumin increased FOXO3a-mediated gene expression by 2-fold, as measured using a FOXO3a-luciferase reporter gene, possibly as a result of influencing FOXO3a phosphorylation and nuclear translocation. The curcumin derivative, tetrahydrocurcumin (THC), which has a similar chemical antioxidant activity as curcumin, did not show any measurable effects. In contrast to the in vitro results, curcumin reduced the lipid levels in peritoneal macrophages in LDL receptor knockout mice fed a high fat diet for four months, suggesting additional regulatory mechanisms in vivo. Thus, the up-regulation of FOXO3a activity by curcumin could be a mechanism to protect against oxidant- and lipid-induced damage in the inflammatory cells of the vascular system.