Recent evidence suggests potential benefits from phytochemicals and micronutrients in protecting against atherosclerosis and inflammation, 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; P < 0.05), leading to increased lipid levels in THP-1 and RAW264.7 monocytes and macrophages (P < 0.05). To investigate the molecular mechanisms involved, we assessed the activity of Forkhead box O3a (FOXO3a), a transcription factor centrally involved in regulating several stress resistance and lipid transport genes. Curcumin increased FOXO3a-mediated gene expression by twofold (P < 0.05), possibly as a result of influencing FOXO3a phosphorylation and nuclear translocation. The curcumin derivative, tetrahydrocurcumin (THC), with similar chemical antioxidant activity as curcumin, did not show any measurable effects. In contrast to the in vitro results, curcumin showed a trend for reduction of lipid levels in peritoneal macrophages in LDL receptor knockout mice fed a high fat diet for 4 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.

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Forkhead box O3a (FOXO3a) is a transcription factor centrally involved in regulating several stress resistance and lipid transport genes. Here we investigated whether the dietary curcumin, a polyphenol in turmeric spice, can modulate FOXO3a activity and the accumulation of lipids in monocytes/macrophages, a process important in atherogenesis. Curcumin in vitro 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 monocytes and macrophages. Curcumin increased FOXO3a activity by 2‐fold, as measured using a FOXO3a‐luciferase reporter gene, possibly as a result of influencing FOXO3a phosphorylation and nuclear translocation. In contrast to the in vitro results, supplementing the high fat diet of LDL receptor knockout mice with curcumin for four months reduced the expression of CD36, aP2, and ATP binding cassette transporter A1 (ABCA1) expression, and lowered the lipid levels in peritoneal macrophages, suggesting involvement of additional regulatory mechanisms in vivo. Thus, the modulation of FOXO3a activity by curcumin could be a mechanism to modulate lipid‐induced stress in the inflammatory cells of the vascular system and reduce the risk for cardiovascular disease. Supported by USDA Contract #58‐1950‐7‐707, and by NIFA/USDA Contract #2010‐65200‐20395.