Tu-P7:18 Intestinal cholesterol absorption is not a major determinant for the age-induced increase in plasma cholesterol in rats

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.

Download Full-text

Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption

International Journal of Obesity ◽

10.1038/ijo.2017.232 ◽

2017 ◽

Vol 42 (3) ◽

pp. 552-560 ◽

Cited By ~ 10

Author(s):

C Blanchard ◽

F Moreau ◽

A Ayer ◽

L Toque ◽

D Garçon ◽

...

Keyword(s):

Gastric Bypass ◽

Plasma Cholesterol ◽

Cholesterol Absorption ◽

Obese Mice ◽

Intestinal Cholesterol Absorption ◽

Cholesterol Excretion

Download Full-text

Phytosterol glycosides reduce cholesterol absorption in humans

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00001.2009 ◽

2009 ◽

Vol 296 (4) ◽

pp. G931-G935 ◽

Cited By ~ 56

Author(s):

Xiaobo Lin ◽

Lina Ma ◽

Susan B. Racette ◽

Catherine L. Anderson Spearie ◽

Richard E. Ostlund

Keyword(s):

Plasma Cholesterol ◽

Cholesterol Absorption ◽

Crossover Design ◽

Whole Body ◽

Soy Lecithin ◽

Intestinal Cholesterol Absorption ◽

Phytosterol Esters ◽

Phytosterol Content ◽

Single Meal ◽

Cholesterol Excretion

Dietary phytosterols inhibit intestinal cholesterol absorption and regulate whole body cholesterol excretion and balance. However, they are biochemically heterogeneous and a portion is glycosylated in some foods with unknown effects on biological activity. We tested the hypothesis that phytosterol glycosides reduce cholesterol absorption in humans. Phytosterol glycosides were extracted and purified from soy lecithin in a novel two-step process. Cholesterol absorption was measured in a series of three single-meal tests given at intervals of 2 wk to each of 11 healthy subjects. In a randomized crossover design, participants received ∼300 mg of added phytosterols in the form of phytosterol glycosides or phytosterol esters, or placebo in a test breakfast also containing 30 mg cholesterol-d7. Cholesterol absorption was estimated by mass spectrometry of plasma cholesterol-d7 enrichment 4–5 days after each test. Compared with the placebo test, phytosterol glycosides reduced cholesterol absorption by 37.6 ± 4.8% ( P < 0.0001) and phytosterol esters 30.6 ± 3.9% ( P = 0.0001). These results suggest that natural phytosterol glycosides purified from lecithin are bioactive in humans and should be included in methods of phytosterol analysis and tables of food phytosterol content.

Download Full-text

Abstract 378: Cholecystokinin Upregulates Cholesterol Absorption in Human Intestinal Epithelial Cells

Circulation Research ◽

10.1161/res.119.suppl_1.378 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Zhongmao Guo ◽

Ningya Zhang ◽

Lemuel Dent ◽

Emmanuel U Okoro ◽

Hong Yang

Keyword(s):

Cell Culture ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Plasma Cholesterol ◽

Cholesterol Absorption ◽

Adherent Cell ◽

Cholesterol Transport ◽

Suspension Cell Culture ◽

Intestinal Epithelial ◽

Intestinal Cholesterol Absorption

Excessive absorption of intestinal cholesterol is a risk factor for atherosclerosis. We previously reported that cholecystokinin (CCK) increases intestinal cholesterol absorption and plasma cholesterol level in mouse models. The goal of this study was to investigate the effect of CCK on cholesterol absorption and Niemann-Pick C1 Like 1 (NPC1L1) expression in human primary intestinal epithelial cells (HPIECs). Normal HPIECs were isolated from small bowl resection specimens, and purchased from the Lonza Group (Walkersville, MD) . Cholesterol absorption was determined by measuring transcellular cholesterol transport in adherent cell culture and cholesterol association and release in suspension cell culture. Surface NPC1L1 was isolated using a biotinylation kit and detected by western blotting. Our data demonstrate that HPIECs express both CCK receptor-1 and -2 (CCK1R; CCK2R). Treatment of HPIECs with 3 nM [Thr28, Nle31]-CCK for 60 min increased transcellular cholesterol transport, cholesterol association and release by ~38, 32 and 44%. Selective inhibition of CCK1R and CCK2R with antagonists (1 μM lorglumide or L365260) or selective knockdown of CCK1R and CCK2R with siRNAs attenuated CCK-induced cholesterol absorption. In the cells cultured on transwell membranes, CCK increased the level of NPC1L1 in the apical membrane by ~35% but did not alter the total NPC1L1 protein expression. Inhibition or knockdown of NPC1L1 attenuated CCK-induced cholesterol absorption. These data imply that activation of CCK1R/2R enhances cholesterol absorption by induction of NPC1L membrane translocation. [This study was supported by NIH grants U54MD0007593, UL1TR000445, and SC1HL101431]

Download Full-text

Dietary cholesterol lowers the activity of butyrylcholinesterase (EC3.1.1.8), but elevates that of esterase-1 (EC3.1.1.1) in plasma of rats

British Journal Of Nutrition ◽

10.1079/bjn19930167 ◽

1993 ◽

Vol 70 (3) ◽

pp. 721-726 ◽

Cited By ~ 11

Author(s):

H. A. Van Lith ◽

A. C. Beynen

Keyword(s):

Cholesterol Metabolism ◽

Plasma Cholesterol ◽

Dietary Cholesterol ◽

Cholesterol Absorption ◽

Intestinal Cholesterol Absorption ◽

Carbohydrate Source ◽

Butyrylcholinesterase Activity

The question addressed is whether an increased intake of cholesterol affects esterase-1 (EC3.1.1.1; ES-1) and butyrylcholinesterase (EC3.1.1.8) activity in plasma. Rats were fed on a purified diet either without or with cholesterol (10 g/kg) added at the expense of the carbohydrate source. Dietary cholesterol significantly decreased plasma butyrylcholinesterase activity, but raised plasma ES-1 activity. Evidence is discussed, suggesting that plasma butyrylcholinesterase is involved in plasma cholesterol metabolism, whereas esterase-1 is involved in intestinal cholesterol absorption.

Download Full-text

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

Bioscience Reports ◽

10.1042/bsr20171162 ◽

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.

Download Full-text

A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Infers How Plant Sterol Intake Reduces Circulating Cholesterol Levels

10.20944/preprints201809.0345.v1 ◽

2018 ◽

Author(s):

Takanari Nakano ◽

Ikuo Inoue ◽

Takayuki Murakoshi

Keyword(s):

Cholesterol Efflux ◽

Plant Sterol ◽

Brush Border Membrane ◽

Plasma Cholesterol ◽

Cholesterol Absorption ◽

Plant Sterols ◽

Intestinal Epithelial ◽

Intestinal Cholesterol Absorption ◽

Cholesterol Levels ◽

Lower Plasma Cholesterol

Hypercholesterolemia accelerates atherosclerosis, and extensive research has been undertaken to ameliorate this abnormality. Plant sterols have been shown to inhibit cholesterol absorption and lower plasma cholesterol level since the 1950s. This ingredient has recently been reappraised as a food additive that can be taken daily in a preclinical period to prevent hypercholesterolemia, considering that cardiovascular-related diseases are the top cause of death globally even with clinical interventions. Intestinal cholesterol handling is still elusive, making it difficult to clarify the mechanism for plant sterol-mediated inhibition. Notably, although the small intestine absorbs cholesterol, it is also the organ that excretes it abundantly, via trans-intestinal cholesterol efflux (TICE). In this review, we show a model where the brush border membrane (BBM) of intestinal epithelial cells stands as the dividing ridge for cholesterol fluxes, making cholesterol absorption and TICE inversely correlated. With this model, we tried to explain the plant sterol-mediated inhibitory mechanism. As well as cholesterol, plant sterols diffuse into the BBM but are effluxed back to the lumen rapidly. We propose that repeated plant sterol shuttling between the BBM and lumen promotes cholesterol efflux, and plant sterol in the BBM may disturb the trafficking machineries that transport cholesterol to the cell interior.

Download Full-text

Lactobacillus acidophilus ATCC 4356 Prevents Atherosclerosis via Inhibition of Intestinal Cholesterol Absorption in Apolipoprotein E-Knockout Mice

Applied and Environmental Microbiology ◽

10.1128/aem.02926-14 ◽

2014 ◽

Vol 80 (24) ◽

pp. 7496-7504 ◽

Cited By ~ 36

Author(s):

Ying Huang ◽

Jinfeng Wang ◽

Guihua Quan ◽

Xiaojun Wang ◽

Longfei Yang ◽

...

Keyword(s):

Apolipoprotein E ◽

Lactobacillus Acidophilus ◽

Plasma Cholesterol ◽

Cholesterol Absorption ◽

Peroxisome Proliferator ◽

Intestinal Cholesterol Absorption ◽

Peroxisome Proliferator Activated Receptor ◽

Content Type ◽

Apolipoprotein E Knockout Mice ◽

Niemann Pick

ABSTRACTThe objective of this study was to investigate the effect ofLactobacillus acidophilusATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. Eight-week-old ApoE−/−mice were fed a Western diet with or withoutL. acidophilusATCC 4356 daily for 16 weeks.L. acidophilusATCC 4356 protected ApoE−/−mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P< 0.05) higher in theL. acidophilusATCC 4356 treatment groups than in the control groups. Furthermore,L. acidophilusATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration ofL. acidophilusATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore,L. acidophilusATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis.

Download Full-text

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90376.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. G873-G885 ◽

Cited By ~ 45

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.

Download Full-text