|Hasan, Syeda -|
|Zingg, Jean-Marc -|
|Kwan, Paul -|
|Noble, Timothy -|
|Smith, Donald -|
|Meydani, Mohsen -|
Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 17, 2013
Publication Date: January 2, 2014
Citation: Hasan, S.T., Zingg, J., Kwan, P., Noble, T., Smith, D., Meydani, M. 2014. Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice. Atherosclerosis. 232(1):40-51. http://dx.doi.org/10.1016/j.atherosclerosis.2013.10.016. Interpretive Summary: Consumption of a high fat diet may result in the development of atherosclerosis, a disease that affects the heart and blood vessels and that also causes accumulation of fat in the liver (steatohepatosis) as well as its dysfunction. Consuming certain naturally occurring substances like spices might be beneficial in treating these conditions. One of the components of the spice turmeric is curcumin, which may help in the body’s processing of lipids, fats found in the bloodstream, and in the suppression of atherosclerosis, a condition that causes fatty deposits to build up in the blood vessels and to narrow them thereby constricting the flow of blood. Building on our previous work with curcumin, we wanted to understand the impact of increasing the doses of curcumin on diseases that were caused by a high fat diet. A mouse model for human cholesterol metabolism was fed either a low fat or high fat diet with increasing low, medium and high doses of curcumin. We found that curcumin reduced weight gain and body fat. At later stages of the study, curcumin increased the amount of fat removed from the body and eliminated through fecal matter. The medium dose of curcumin reduced the formation of fat deposits in the heart, the liver and the bloodstream. Of interest, the high dose had a negative effect on these same outcomes in the heart and bloodstream but they had a positive effect of suppressing the development of fatty liver. Our research thus far indicates that certain naturally occurring substances may be used to alleviate conditions caused by high fat diets, but that the dosage of these substances must be investigated to determine the most effective dose.
Technical Abstract: Consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherogenesis. Fatty acid binding proteins (FABP-4/aP2) and CD36 expression are key factors in lipid accumulation in macrophages and foam cell formation in atherogenesis. Our earlier observations suggest that curcumin’s suppression of atherogenesis might be mediated through suppression of aP2 and CD36 expression in macrophages. Thus, this study aimed to further elucidate the impact of increasing doses of curcumin on modulation of these molecular mediators on high fat diet-induced atherogenesis, inflammation, and steatohepatosis in LDLr mice. LDLr mice were fed low fat (LF) or high fat (HF) diet supplemented with curcumin (500 HF plus LC; 1,000 HF plus MC; 1,500 HF plus HC mg/kg diet) for 16 wks. Fecal samples were analyzed for total lipid content. Lipids accumulation in THP-1 cells and expression of aP2, CD36 and lipid accumulation in peritoneal macrophages were measured. Fatty streak lesions and expression of IL-6 and MCP-1 in descending aortas were quantified. Aortic root were stained for fatty and fibrotic deposits and for the expression of aP2 and VCAM-1. Total free fatty acids, insulin, glucose, triglycerides, and cholesterol as well as several inflammatory markers including IL-1, IL-6, IL-10, IL-12p70, KC/GRO, TNF-alpha and IFN-gamma were measured in plasma. The liver’s total lipids, cholesterol, triglycerides, and HDL content were measured, and the presence of fat droplets, peri-portal fibrosis and glycogen were examined histologically. Curcumin dose-dependently reduced accumulation of oxLDL in THP-1 cells. Curcumin also reduced body weight gain and body fat without affecting fat distribution. During early intervention, curcumin decreased fecal fat, but at later stages, it increased fat excretion. Curcumin at medium dose (HF plus MC) was significantly effective at reducing fatty streak formation and suppressing aortic expression of IL-6, MCP-1 in the descending aorta and blood levels of several inflammatory cytokines, but at a higher dose (HF plus HC, 1,500 mg/kg diet), it had adverse effects on these parameters. This trend was also present when aortic root sections were examined histologically. However, at a high dose, curcumin suppressed development of steatohepatosis, reduced fibrotic tissue, and preserved glycogen levels in liver. Curcumin through a series of complex mechanisms, alleviated the adverse effects of high fat diet on weight gain, fatty liver development, dyslipidemia, expression of inflammatory cytokines and atherosclerosis in LDLr mouse model of human atherosclerosis. One of the mechanisms by which curcumin modulates atherogenesis is through suppression of aP2 and CD36 expression in macrophages, which are the key players in atherogenesis. Overall, these effects of curcumin are dose-dependent; specifically, a medium dose of curcumin in HF diet appears to be more effective than a higher dose of curcumin.