Modulation of cAMP levels by high fat diet and curcumin and regulatory effects on CD36/FAT scavenger receptor/fatty acids transporter gene expression

Authors: ZINGG, JEAN-MARC - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HASAN, SYEDA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; NAKAGAWA, KIYOTAKA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CANEPA, ELISA - University Of Genoa; RICCIARELLI, ROBERTA - University Of Genoa; VILLACORTA, LUIS - University Of Michigan; AZZI, ANGELO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MEYDANI, MOHSEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Biofactors
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/3/2016
Publication Date: 6/29/2016
Citation: Zingg, J-M., Hasan, S.T., Nakagawa, K., Canepa, E., Ricciarelli, R., Villacorta, L., Azzi, A., Meydani, M. 2016. Modulation of cAMP levels by high fat diet and curcumin and regulatory effects on CD36/FAT scavenger receptor/fatty acids transporter gene expression. Biofactors. doi: 10.1002/biof.1307.

Interpretive Summary: Turmeric is a spice that has been used traditionally in Asian countries to prevent and treat many diseases. Curcumin, which is found in the root area of the spice plant, helps to lower levels of lipids or fats in the bloodstream as well as lower the occurrence of obesity and atherosclerosis, a condition in which fat builds up in the blood vessels and constricts blood flow. Learning the molecular mechanisms by which curcumin is able to do this would help researchers develop accurate treatments for its use. In this study using cell cultures and in vivo animal models, we have investigated whether the expression of a number of genes involved in maintaining a healthy balance of fat could be affected by curcumin. We used a mouse model that is prone to high levels of fat and atherosclerosis, a condition in which fat builds up in the blood vessels. Our study results suggest that curcumin is able to modify gene expression, which, in turn, prevents inflammation and the build-up of fat in the blood vessels. Our data further suggest that curcumin suppresses the concentration of fat in the liver. Confirming that consuming curcumin has a positive effect on the liver suggests the use of this component of turmeric to help lower plasma lipid and cholesterol.

Technical Abstract: Curcumin, a polyphenol from turmeric (Curcuma longa), reduces inflammation, atherosclerosis, and obesity in several animal studies. In Ldlr-/- mice fed a high-fat diet (HFD), curcumin reduces plasma lipid levels, therefore contributing to a lower accumulation of lipids and to reduced expression of fatty acid transport proteins (CD36/FAT, FABP4/aP2) in peritoneal macrophages. In this study, we analyzed the molecular mechanisms by which curcumin (500, 1000, 1500 mg/kg diet, for 4 months) may influence plasma and tissue lipid levels in Ldlr-/- mice fed an HFD. In liver, HFD significantly suppressed cAMP levels, and curcumin restored almost normal levels. Similar trends were observed in adipose tissues, but not in brain, skeletal muscle, spleen, and kidney. Treatment with curcumin increased phosphorylation of CREB in liver, what may play a role in regulatory effects of curcumin in lipid homeostasis. In cell lines, curcumin increased the level of cAMP, activated the transcription factor CREB and the human CD36 promoter via a sequence containing a consensus CREB response element. Regulatory effects of HFD and Cur on gene expression were observed in liver, less in skeletal muscle and not in brain. Since the cAMP/protein kinase A (PKA)/CREB pathway plays an important role in lipid homeostasis, energy expenditure, and thermogenesis by increasing lipolysis and fatty acid beta-oxidation, an increase in cAMP levels induced by curcumin may contribute to its hypolipidemic and anti-atherosclerotic effects.