scholarly journals SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin

2011 ◽  
Vol 301 (1) ◽  
pp. G148-G155 ◽  
Author(s):  
Pradeep Kumar ◽  
Pooja Malhotra ◽  
Ke Ma ◽  
Amika Singla ◽  
Omar Hedroug ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Promoter Activity ◽  
Plasma Cholesterol ◽  
Biological Effects ◽  
Cholesterol Absorption ◽  
Inhibitory Effect ◽  
Cholesterol Homeostasis ◽  
Cholesterol Esterification ◽  
Dependent Manner ◽  
Intestinal Cholesterol Absorption

Curcumin, the major phenolic compound in the spice turmeric, exhibits numerous biological effects, including lowering plasma cholesterol and preventing diet-induced hypercholesterolemia. The mechanisms underlying the hypocholesterolemic effect of curcumin are not fully understood. In this regard, intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter, the molecular target of intestinal cholesterol absorption inhibitor ezetimibe, plays an essential role in the maintenance of cholesterol homeostasis. The current studies were designed to investigate the effect of curcumin on NPC1L1 function, expression, and promoter activity in intestinal Caco-2 monolayers. NPC1L1 function was evaluated by the measurement of ezetimibe-sensitive [3H]cholesterol esterification. Relative abundance of NPC1L1 mRNA and protein was evaluated by real-time PCR and Western blotting, respectively. Luciferase assays were used to measure NPC1L1 promoter activity. Our results showed that curcumin significantly inhibited ezetimibe-sensitive cholesterol esterification in a dose-dependent manner with a maximum decrease (by 52% compared with control) occurring at 50 μM concentration. Curcumin treatment of Caco-2 monolayers also significantly decreased NPC1L1 mRNA and protein expression. Similarly, the promoter activity of the NPC1L1 gene was inhibited significantly (55%) by 50 μM curcumin. The decrease in NPC1L1 promoter activity by curcumin was associated with a reduction in the expression and the DNA-binding activity of the sterol response element-binding protein 2 (SREBP2) transcription factor. Furthermore, the overexpression of active SREBP2 protected NPC1L1 from the inhibitory effect of curcumin. Our studies demonstrate that curcumin directly modulates intestinal NPC1L1 expression via transcriptional regulation and the involvement of SREBP2 transcription factor.

scholarly journals Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Line Zurkinden ◽  
Dmitri Sviridov ◽  
Bruno Vogt ◽  
Geneviève Escher
Keyword(s):  
Plasma Lipids ◽  
Gene Dosage ◽  
Plasma Cholesterol ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Protective Mechanism ◽  
Intestinal Cholesterol Absorption ◽  
Apoe Ko Mice ◽  
Apoe Ko

Sterol 27-hydroxylase (CYP27A1) catalyzes the hydroxylation of cholesterol to 27-hydroxycholesterol (27-OHC) and regulates cholesterol homeostasis. In Cyp27a1/ Apolipoprotein E (ApoE) double knockout (KO) mice fed with Western diet (WD), the atherosclerotic phenotype found in ApoE KO mice was reversed. As protective mechanism, up-regulation of Cyp3a11 and Cyp7a1 was proposed. Cyp27a1 heterozygote/ApoE KO (het) mice, with reduced Cyp27a1 expression and normal levels of Cyp7a1 and Cyp3a11, developed more severe lesions than ApoE KO mice. To analyze the contribution of Cyp3a11 to the protection of atherosclerosis development, Cyp3a11 was induced by Rifampicin (RIF) in ApoE KO and het mice. Males were fed with WD and treated daily with RIF (10 mg/kg ip) or vehicle for 4 weeks. Atherosclerosis was quantified in the aortic valve. Plasma lipids and 27-hydroxycholesterol (27-OHC), expression of cytochromes P450 and genes involved in cholesterol transport and bile acids (BAs) signaling in liver and intestine, and intestinal cholesterol absorption were analyzed. RIF increased expression of hepatic but not intestinal Cyp3a11 4-fold in both genotypes. In ApoE KO mice treated with RIF, we found a 2-fold decrease in plasma cholesterol, and a 2-fold increase in high-density lipoprotein/low-density lipoprotein ratio and CY27A1 activity. Intestinal cholesterol absorption remained unchanged and atherosclerotic lesions decreased approximately 3-fold. In het mice, RIF had no effect on plasma lipids composition, CYP27A1 activity, and atherosclerotic plaque development, despite a reduction in cholesterol absorption. In conclusion, the antiatherogenic effect of Cyp3a11 induction by RIF was also dependent on Cyp27a1 expression.

Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors

2008 ◽  
Vol 295 (5) ◽  
pp. G873-G885 ◽  
Author(s):  
Z. Ravid ◽  
M. Bendayan ◽  
E. Delvin ◽  
A. T. Sane ◽  
M. Elchebly ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Expression ◽  
High Glucose ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Cholesterol Transport ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Uptake ◽  
Glucose Levels

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [14C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose ( P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of intestinal cholesterol transport. The high concentration of glucose enhanced the protein expression of the critical cholesterol transporter NPC1L1 and that of CD36 ( P < 0.02) and concomitantly decreased SR-BI protein mass ( P < 0.02). No significant changes were observed in the protein expression of ABCA1 and ABCG8, which act as efflux pumps favoring cholesterol export out of absorptive cells. At the same time, 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was decreased ( P < 0.007), whereas ACAT activity remained unchanged. Finally, increases were noted in the transcription factors LXR-α, LXR-β, PPAR-β, and PPAR-γ along with a drop in the protein expression of SREBP-2. Collectively, our data indicate that glucose at high concentrations may regulate intestinal cholesterol transport and metabolism in Caco-2/15 cells, thus suggesting a potential influence on the cholesterol absorption process in Type 2 diabetes.

scholarly journals Involvement of the arachidonic acid cytochrome P450 epoxygenase pathway in the proliferation and invasion of human multiple myeloma cells

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1925 ◽  
Author(s):  
Jing Shao ◽  
Hongxiang Wang ◽  
Guolin Yuan ◽  
Zhichao Chen ◽  
Qiubai Li
Keyword(s):  
Multiple Myeloma ◽  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Biological Effects ◽  
Inhibitory Effect ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
The Matrix ◽  
Human Multiple Myeloma ◽  
Proliferation And Invasion

Cytochrome P450 (CYP) epoxygenases and the metabolites epoxyeicosatrienoic acids (EETs) exert multiple biological effects in various malignancies. We have previously found EETs to be secreted by multiple myeloma (MM) cells and to be involved in MM angiogenesis, but the role of the arachidonic acid cytochrome P450 epoxygenase pathway in the proliferation and mobility of MM cells remains unknown. In the present study, we found that MM cell lines generated detectable levels of 11,12-EET/14,15-EET and that increased levels of EETs were found in the serum of MM patients compared to healthy donors. The addition of exogenous EETs induced significantly enhanced proliferation of MM cells, whereas 17-octadecynoic acid (17-ODYA), an inhibitor of the CYP epoxygenase pathway, inhibited the viability and proliferation of MM cells. Moreover, this inhibitory effect could be successfully reversed by exogenous EETs. 17-ODYA also inhibited the motility of MM cells in a time-dependent manner, with a reduction of the gelatinolytic activity and protein expression of the matrix metalloproteinases (MMP)-2 and MMP-9. These results suggest the CYP epoxygenase pathway to be involved in the proliferation and invasion of MM cells, for which 17-ODYA could be a promising therapeutic drug.

scholarly journals Mechanisms of cholesterol-lowering effects of dietary insoluble fibres: relationships with intestinal and hepatic cholesterol parameters

2005 ◽  
Vol 94 (3) ◽  
pp. 331-337 ◽  
Author(s):  
Ariëtte M. van Bennekum ◽  
David V. Nguyen ◽  
Georg Schulthess ◽  
Helmut Hauser ◽  
Michael C. Phillips
Keyword(s):  
Bile Acid ◽  
Food Intake ◽  
Serum Cholesterol ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Hepatic Cholesterol ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Lowering ◽  
Dietary Fibres ◽  
Bile Acid Binding

Fibres with a range of abilities to perturb cholesterol homeostasis were used to investigate how the serum cholesterol-lowering effects of insoluble dietary fibres are related to parameters of intestinal cholesterol absorption and hepatic cholesterol homeostasis in mice. Cholestyramine, chitosan and cellulose were used as examples of fibres with high, intermediate and low bile acid-binding capacities, respectively. The serum cholesterol levels in a control group of mice fed a high fat/high cholesterol (HFHC) diet for 3 weeks increased about 2-fold to 4·3 mm and inclusion of any of these fibres at 7·5 % of the diet prevented this increase from occurring. In addition, the amount of cholesterol accumulated in hepatic stores due to the HFHC diet was reduced by treatment with these fibres. The three kinds of fibres showed similar hypocholesterolaemic activity; however, cholesterol depletion of liver tissue was greatest with cholestyramine. The mechanisms underlying the cholesterol-lowering effect of cholestyramine were (1) decreased cholesterol (food) intake, (2) decreased cholesterol absorption efficiency, and (3) increased faecal bile acid and cholesterol excretion. The latter effects can be attributed to the high bile acid-binding capacity of cholestyramine. In contrast, incorporation of chitosan or cellulose in the diet reduced cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. The present study provides strong evidence that above all satiation and satiety effects underlie the cholesterol-lowering properties of insoluble dietary fibres with moderate or low bile acid-binding capabilities.

scholarly journals Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation

2011 ◽  
Vol 53 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Tam M. Nguyen ◽  
Janet K. Sawyer ◽  
Kathryn L. Kelley ◽  
Matthew A. Davis ◽  
Lawrence L. Rudel
Keyword(s):  
Cholesterol Absorption ◽  
Cholesterol Esterification ◽  
Intestinal Cholesterol Absorption ◽  
Lymph Duct

scholarly journals Disodium ascorbyl phytostanol phosphate (FM-VP4), a modified phytostanol, is a highly active hypocholesterolaemic agent that affects the enterohepatic circulation of both cholesterol and bile acids in mice

2009 ◽  
Vol 103 (2) ◽  
pp. 153-160 ◽  
Author(s):  
J. Méndez-González ◽  
S. Süren-Castillo ◽  
L. Calpe-Berdiel ◽  
N. Rotllan ◽  
M. Vázquez-Carrera ◽  
...  
Keyword(s):  
Bile Acid ◽  
Target Genes ◽  
Enterohepatic Circulation ◽  
Acid Output ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Farnesoid X Receptor ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism ◽  
Intestinal Cholesterol Absorption

Disodium ascorbyl phytostanol phosphate (FM-VP4) is a synthetic compound derived from sitostanol and campestanol that has proved to be efficient as a cholesterol-lowering therapy in mice and human subjects. However, the mechanism of action of FM-VP4 remains unknown. The present study tests the ability of FM-VP4 to alter intestinal and liver cholesterol homeostasis in mice. Female C57BL/6J mice were fed either a control chow or a 2 % FM-VP4-enriched diet for 4 weeks. FM-VP4 reduced the in vivo net intestinal cholesterol absorption and plasma and liver cholesterol concentrations by 2·2-, 1·5- and 1·6-fold, respectively, compared with control mice. Furthermore, FM-VP4 also showed an impact on bile acid homeostasis. In FM-VP4 mice, liver and intestinal bile acid content was increased by 1·3- and 2·3-fold, respectively, whereas faecal bile acid output was 3·3-fold lower. FM-VP4 also increased the intestinal absorption of orally administered [3H]taurocholic acid to small intestine in vivo. Inhibition of intestinal cholesterol absorption by FM-VP4 was not mediated via transcriptional increases in intestine liver X receptor (LXR)-α, adenosine triphosphate-binding cassette transporter (ABC)-A1, ABCG5/G8 nor to decreases in intestinal Niemann-Pick C1-like 1 (NPC1L1) expression. In contrast, FM-VP4 up-regulated liver LXRα, ABCA1, ABCG5, scavenger receptor class BI (SR-BI) and hydroxymethylglutaryl coenzyme A reductase (HMGCoA-R) gene expression, whereas it down-regulated several farnesoid X receptor (FXR)-target genes such as cytochrome P450 family 7 subfamily A polypeptide 1 (CYP7A1) and Na+/taurocholate co-transporter polypeptide (NTCP). In conclusion, FM-VP4 reduced intestinal cholesterol absorption, plasma and liver cholesterol and affected bile acid homeostasis by inducing bile acid intestinal reabsorption and changed the liver expression of genes that play an essential role in cholesterol homeostasis. This is the first phytosterol or stanol that affects bile acid metabolism and lowers plasma cholesterol levels in normocholesterolaemic mice.

Abstract 129: Liver-Specific and Intestine-Specific ACAT2 Knockout Mice Are Equally Protected from Diet-Induced Hepatic Cholesterol Accumulation

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Jun Zhang ◽  
Kathryn Kelley ◽  
Stephanie Marshall ◽  
Matthew Davis ◽  
Martha Wilson ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Cholesterol Accumulation ◽  
Very Low Density Lipoproteins ◽  
Plasma Triglycerides ◽  
Hepatic Lipid Accumulation ◽  
Vldl Cholesterol

Acyl-CoA:cholesterol acyltransferase 2 (ACAT2) is exclusively expressed in the small intestine and liver. ACAT2 facilitates the movement of cholesterol among tissues by generating cholesteryl ester (CE) for packaging into newly synthesized chylomicrons and very low-density lipoproteins (VLDL). In these studies we investigated whether CE derived from either the intestine or liver would differentially affect hepatic and plasma cholesterol homeostasis. For this purpose, we generated both liver-specific (ACAT2L-/L-) and intestine-specific (ACAT2SI-/SI-) ACAT2 knockout mice, and studied dietary cholesterol-induced hepatic lipid accumulation and hypercholesterolemia. Interestingly, diet-induced accumulation of hepatic CE was similarly decreased in both ACAT2L-/L- and ACAT2SI-/SI- mice, and free cholesterol did not build up in the liver. Compared with control mice, both ACAT2L-/L- and ACAT2SI-/SI- mice had lower levels of plasma VLDL-cholesterol but higher plasma triglycerides. ACAT2SI-/SI- but not ACAT2L-/L- mice had blunted cholesterol absorption. Collectively, both ACAT2L-/L- and ACAT2SI-/SI- mice were equally protected from diet-induced hepatic CE accumulation and hypercholesterolemia. These results suggest that inhibition of either intestinal or hepatic ACAT2 improves atherogenic hyperlipidemia and limits hepatic CE accumulation in mice, indicating that inhibition of ACAT2 expression in either tissue likely would be beneficial for atheroprotection.

scholarly journals Plasma Cholesterol-Lowering Activity of Soybean Germ Phytosterols

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2784 ◽  
Author(s):  
Hanyue Zhu ◽  
Jingnan Chen ◽  
Zouyan He ◽  
Wangjun Hao ◽  
Jianhui Liu ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Cholesterol Absorption ◽  
High Cholesterol Diet ◽  
Dependent Manner ◽  
Cholesterol Diet ◽  
Cholesterol Lowering ◽  
Underlying Mechanisms ◽  
Sterol Excretion ◽  
Dose Dependent ◽  
Lowering Activity

Soybean germ phytosterols (SGP) largely exist in soybean germ oil. Our previous study demonstrated that soybean germ oil was effective in reducing plasma cholesterol. However, it remains unknown if its phytosterols are the active ingredients responsible for the plasma cholesterol-lowering activity. The present study aimed to test the effect of SGP on plasma cholesterol and to investigate its associated underlying mechanisms using hamsters as animal model. Male hamsters (n = 40) were randomly divided into five groups (n = 8/group) and fed one of the five diets: a non-cholesterol diet (NCD), a high cholesterol diet (HCD), a HCD diet containing 0.5% cholestyramine (PC), and two HCD diets containing 0.1% (LP) and 0.2% (HP) SGP, respectively, for six weeks. Results showed that SPG reduced plasma cholesterol level in a dose-dependent manner, whereas it dose-dependently increased the excretion of both fecal neutral and acidic sterols. SGP was also effective in displacing cholesterol from micelles. It was concluded that SGP possessed hypocholesterolemic activity, likely by inhibiting cholesterol absorption in the intestine and promoting fecal sterol excretion.

scholarly journals The Impact of Egg Nutrient Composition and Its Consumption on Cholesterol Homeostasis

Cholesterol ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Heqian Kuang ◽  
Fang Yang ◽  
Yan Zhang ◽  
Tiannan Wang ◽  
Guoxun Chen
Keyword(s):  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Nutrient Deficiencies ◽  
Intestinal Cholesterol Absorption ◽  
Lipid Molecule ◽  
Egg Consumption ◽  
Elevated Cholesterol ◽  
Potential Benefits ◽  
Nutritional Needs ◽  
The Impact

Nutrient deficiencies and excess are involved in many aspects of human health. As a source of essential nutrients, eggs have been used worldwide to support the nutritional needs of human societies. On the other hand, eggs also contain a significant amount of cholesterol, a lipid molecule that has been associated with the development of cardiovascular diseases. Whether the increase of egg consumption will lead to elevated cholesterol absorption and disruption of cholesterol homeostasis has been a concern of debate for a while. Cholesterol homeostasis is regulated through its dietary intake, endogenous biosynthesis, utilization, and excretion. Recently, some research interests have been paid to the effects of egg consumption on cholesterol homeostasis through the intestinal cholesterol absorption. Nutrient components in eggs such as phospholipids may contribute to this process. The goals of this review are to summarize the recent progress in this area and to discuss some potential benefits of egg consumption.

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