Curcumin Up-Regulates LDL Receptor Expression via the Sterol Regulatory Element Pathway in HepG2 Cells

Dou, Xiaobing; Fan, Chunlei; Wo, Li‐Ke; Yan, Jin; Qian, Ying; Xing-de, WO

doi:10.1055/s-2008-1081316

Cited by 39 publications

(37 citation statements)

References 13 publications

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“…Similar to that, an increase of lipids was observed in hepatic stellate cells (HSC) [Tang and Chen, 2010], whereas in activated HSC, curcumin suppressed LDL receptor expression via a sterol regulatory element (SRE) [Kang and Chen, 2009]. However, in HepG2 cells, curcumin activated LDL receptor expression which has been proposed to contribute its cholesterol lowering and anti-atherosclerotic effects [Dou et al, 2008]. In skeletal muscle, curcumin increased the expression and membrane exposition of CD36 [Bastie et al, 2005;Na et al, 2011], possibly via activation of FOXO1 [Nahle et al, 2008], whereas in HepG2 cells, CD36 expression was reduced by curcumin [Peschel et al, 2007].…”

supporting

confidence: 56%

“…We observed in a previous study with male C57BL/6 mice on a high fat Western style diet for 12 weeks that curcumin reduced plasma levels of free fatty acids, triglycerides, and cholesterol, possibly explaining the lower lipid accumulation seen here in peritoneal macrophages in response to curcumin [Ejaz et al, 2009]. In fact, increased removal of lipids from circulation by up-regulating the LDL receptor may contribute to the cholesterol lowering and anti-atherosclerotic effects of curcumin in these mice [Dou et al, 2008]; however, since we used LDL-R À/À mice, additional mechanisms may be the basis for the reduction of lipid accumulation by curcumin in peritoneal macrophages isolated from these mice.…”

Section: Discussionmentioning

confidence: 57%

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Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages

Zingg

Hasan

Cowan

et al. 2012

J of Cellular Biochemistry

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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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supporting

confidence: 56%

Section: Discussionmentioning

confidence: 57%

Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages

Zingg

Hasan

Cowan

et al. 2012

J of Cellular Biochemistry

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“…Similar reductions were also identified thereafter in diabetic animals and animals fed high fat [10-12] and in healthy humans, varied with the dose, age and the period of administration [13-15]. The mechanism underlying the hypocholesterolemic effect may be related to the upregulation of LDL receptor [16,17]. Since plasma cholesterol levels are also influenced by absorption of cholesterol in the gut, we, in the present study, addressed a question whether curcumin affects the cholesterol uptake in the enterocytes.…”

Section: Introductionmentioning

confidence: 70%

Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression

2010

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BackgroundCurcumin is a polyphenol and the one of the principle curcuminoids of the spice turmeric. Its antioxidant, anti-cancer and anti-inflammatory effects have been intensively studied. Previous in vivo studies showed that administration of curcumin also decreased cholesterol levels in the blood, and the effects were considered to be related to upregulation of LDL receptor. However, since plasma cholesterol levels are also influenced by the uptake of cholesterol in the gut, which is mediated by a specific transporter Niemann-Pick Cl-like 1 (NPC1L1) protein, the present study is to investigate whether curcumin affects cholesterol uptake in the intestinal Caco-2 cells.MethodsCaco-2 cells were cultured to confluence. The micelles composed of bile salt, monoolein, and 14C-cholesterol were prepared. We first incubated the cells with the micelles in the presence and absence of ezetimibe, the specific inhibitor of NPC1L1, to see whether the uptake of the cholesterol in the cells was mediated by NPC1L1. We then pretreated the cells with curcumin at different concentrations for 24 h followed by examination of the changes of cholesterol uptake in these curcumin-treated cells. Finally we determined whether curcumin affects the expression of NPC1L1 by both Western blot analysis and qPCR quantification.ResultsWe found that the uptake of radioactive cholesterol in Caco-2 cells was inhibited by ezetimibe in a dose-dependent manner. The results indicate that the uptake of cholesterol in this study was mediated by NPC1L1. We then pretreated the cells with 25-100 μM curcumin for 24 h and found that such a treatment dose-dependently inhibited cholesterol uptake with 40% inhibition obtained by 100 μM curcumin. In addition, we found that the curcumin-induced inhibition of cholesterol uptake was associated with significant decrease in the levels of NPC1L1 protein and NPC1L1 mRNA, as analyzed by Western blot and qPCR, respectively.ConclusionCurcumin inhibits cholesterol uptake through suppression of NPC1L1 expression in the intestinal cells.

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“…There may be three possible reasons. Some studies indicated that curcumin up-regulated the expression of low-intensity lipoprotein receptor (LDL-R) protein in human lymphocytes, HEK-293 and mouse macrophages [25]–[30]. Liposoluble sensitizers likely enter cells through LDL-R, while both curcumin and Hydroxyl acetylated curcumin are defined as liposoluble sensitizers.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis of THP-1 Derived Macrophages Induced by Sonodynamic Therapy Using a New Sonosensitizer Hydroxyl Acetylated Curcumin

et al. 2014

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Curcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa. Our previous study indicated curcumin was able to function as a sonosensitizer. Hydroxyl acylated curcumin was synthesized from curcumin to eliminate the unstable hydroxy perssad in our group. The potential use of Hydroxyl acylated curcumin as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. This study investigated the sonodynamic effect of Hydroxyl acylated curcumin on THP-1 macrophage. THP-1 macrophages were cultured with Hydroxyl acylated curcumin at a concentration of 5.0 μg/mL for 4 hours and then exposed to pulse ultrasound irradiation (0.5 W/cm2 with 1.0 MHz ) for 5 min, 10 min and 15 min. Six hours later, cell viability decreased significantly by CCK-8 assay. After ultrasound irradiation, the ratio of apoptosis and necrosis in SDT group was higher than that in control, Hydroxyl acylated curcumin alone and ultrasound alone. Moreover, the apoptotic rate was higher than necrotic rate with the flow cytometry analysis. Furthermore, Hydroxyl acylated curcumin-SDT induced reactive oxygen species (ROS) generation in THP-1 macrophages immediately after the ultrasound treatment while ROS generation was reduced significantly with the scavenger of singlet oxygen Sodium azide (NaN3). Hydroxyl acylated curcumin-SDT led to a conspicuous loss of mitochondrial membrane potential (MMP) compared with other groups, while MMP was increased significantly with the scavenger of singlet oxygen Sodium azide (NaN3), ROS inhibitor N-acetyl cysteine (NAC) and Mitochondrial Permeability Transition Pore (MPTP) inhibitor Cyclosporin A (CsA). The cytochrome C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP upregulated after SDT through Western blotting. These findings suggested that Hydroxyl acylated curcumin under low-intensity ultrasound had sonodynamic effect on THP-1 macrophages via generation of intracellular singlet oxygen and mitochondria-caspase signaling pathway, indicating that Hydroxyl acylated curcumin could be used as a novel sonosensitizer in SDT for atherosclerosis.

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Curcumin Up-Regulates LDL Receptor Expression via the Sterol Regulatory Element Pathway in HepG2 Cells

Cited by 39 publications

References 13 publications

Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages

Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages

Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression

Apoptosis of THP-1 Derived Macrophages Induced by Sonodynamic Therapy Using a New Sonosensitizer Hydroxyl Acetylated Curcumin

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