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  • Curcumin is a polyphenol extracted from turmeric which is co


    Curcumin is a polyphenol extracted from turmeric, which is commonly used as a spice and food-coloring agent in many cultures [9]. Curcumin possesses anti-inflammatory, antioxidant, and cancer-preventive properties [10], [11], [12]. In addition to these well-known effects, consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherosclerosis. Many studies in animals and humans have demonstrated that curcumin supplementation exerts hypocholesterolemic effects [13], [14], [15], [16], [17]. Furthermore, the antiatherogenic effects of curcumin have recently been demonstrated in animal models [18], [19], [20]. Shin et al showed that long-term curcumin administration lowered blood and hepatic cholesterol and prevented the development of atherosclerosis in LDLR−/− mice [19]. In rabbits fed a high-cholesterol diet, curcumin supplementation reduced oxidative stress and suppressed the formation of aortic fatty streaks [18]. High cholesterol is an important risk factor for atherosclerosis, and reduced cholesterol osmi has been found to cause a decrease in plasma cholesterol levels and atherosclerosis formation [8], [21]. Previously, we reported that curcumin treatment exhibits a hypocholesterolemic effect in high-fat–fed hamsters via the inhibition of intestinal cholesterol absorption, which is mediated by the downregulation of intestinal NPC1L1 [14]. Therefore, based on the previous studies, we hypothesized that curcumin supplementation can reduce intestinal cholesterol absorption in ApoE knockout (ApoE−/−) mice and prevent atherosclerosis development. To test our hypothesis, we used high-fat diet–fed ApoE−/− mice, genetically modified mice commonly used as the animal model for spontaneous atherosclerosis, to examine the effects of curcumin supplementation on intestinal NPC1L1 expression and cholesterol absorption, aortic cholesterol accumulation, and atherosclerotic development in aortic sinus.
    Methods and materials
    Discussion Our earlier study noted that curcumin inhibited cholesterol uptake via the Caco-2 cells, which could have been partly attributed to curcumin's suppression of NPC1L1 [27], a key player in cholesterol absorption. We recently reported that curcumin exerts a hypocholesterolemic effect in high-fat–fed hamsters through downregulating NPC1L1 expression and reducing intestinal cholesterol absorption [14]. Hypercholesterolemia is a significant risk factor for atherosclerosis and coronary heart disease; whether curcumin through the inhibition of cholesterol absorption prevents the accumulation of cholesterol in the aortas and the development of atherosclerosis is therefore an important question to be assessed. Our current results demonstrated that curcumin exhibited an atheroprotective effect in ApoE−/− mice by lowering circulating atherogenic cholesterol-containing lipoproteins and cholesterol accumulation in aortas. Interestingly, the antiatherogenic and cholesterol-lowering effects of curcumin coincided with a significant decrease in intestinal cholesterol absorption. Decreased cholesterol absorption was mediated by inhibiting the intestinal expression of NPC1L1, predominantly in the duodenal and jejunal segments of the small intestine, where most of the cholesterol absorption takes place. The hypocholesterolemic effect of curcumin was previously considered to be related to the regulation of hepatic osmi LDL receptor, HMG-CoA reductase, and cholesterol 7α-hydroxylase (CYP7A1) [19], [28], [29], [30]. Several studies have indicated that curcumin upregulated LDL receptor expression and increased the uptake activity of LDL receptors [28], [30], resulting in increased cholesterol clearance from the body. Curcumin has also been found to suppress HMG-CoA reductase activity and has an inhibitory effect on hepatic cholesterol biosynthesis [19]. Curcumin's cholesterol-lowering feature could also be attributed to the increase of CYP7A1 activity in the liver. Enhanced CYP7A1 activity results in increased cholesterol excretion, which in turn decreases cholesterol levels [29]. In contrast to previous studies, our present results indicated that curcumin was able to lower cholesterol levels by reducing cholesterol absorption via the downregulation of intestinal NPC1L1 expression. Indeed, curcumin is poorly absorbed and its plasma concentration is very low; thus, the inhibition of intestinal cholesterol absorption may be mainly responsible for the cholesterol-lowering effect of curcumin. Moreover, NPC1L1 has recently been identified as a target of the ezetimibe, which selectively inhibits the intestinal absorption of dietary and biliary cholesterol [31]. Ezetimibe is an effective cholesterol-lowering drug and has been widely used for treating hypercholesterolemia [32]. We previously found that the inhibitory effect of curcumin on cholesterol absorption was equivalent to ezetimibe; curcumin will be a potent cholesterol-lowering nutrient through inhibiting cholesterol absorption. Additionally, it is worth noting that ABCG5/ABCG8 and ACAT2 also play important roles in intestinal cholesterol metabolism. Contrary to the function of intestinal NPC1L1, ABCG5/ABCG8 transports cholesterol from the enterocytes into the gut lumen for fecal disposal [33]. Mice overexpressing ABCG5/ABCG8 exhibit a 50% decrease in dietary cholesterol absorption [34]. ACAT2 encodes acyl-coenzyme A acyltransferase enzymes responsible for the formation of cholesteryl esters. Lack of ACAT2−/− leads to lower cholesterol esterification and prevents atherosclerosis [35]. However, we observed no effect of curcumin on intestinal ABCG5/ABCG8 or ACAT2 expression. Consistent with our studies, Ding and Shin also did not observe any change in hepatic ABCG5/ABCG8 or ACAT2 expression in mice after long-term curcumin treatment [19], [36]. Therefore, curcumin appears to lower cholesterol in ApoE−/− mice independent of changes in intestinal ABCG5/ABCG8 or ACAT2 expression. Our current results suggest that the inhibition of curcumin on cholesterol absorption in ApoE−/− mice may be mediated by the downregulation of NPC1L1 expression, and the ability of curcumin to attenuate atherosclerosis may be associated with its effect on cholesterol absorption.