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

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.

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Hypocholesterolaemic effects of plant sterol analogues are independent of ABCG5 and ABCG8 transporter expressions in hamsters

British Journal Of Nutrition ◽

10.1017/s0007114507721517 ◽

2007 ◽

Vol 98 (3) ◽

pp. 550-555 ◽

Cited By ~ 14

Author(s):

Xiaoming Jia ◽

Naoyuki Ebine ◽

Isabelle Demonty ◽

Yanwen Wang ◽

Robin Beech ◽

...

Keyword(s):

Small Intestine ◽

Mrna Expression ◽

Plant Sterol ◽

Plasma Cholesterol ◽

Plant Sterols ◽

Lower Plasma ◽

Plant Stanols ◽

Cholesterol Levels ◽

Lower Plasma Cholesterol ◽

Reduce Plasma Cholesterol

The hypolipidaemic effects of plant sterols are well established. However, mechanisms by which plant sterols lower plasma cholesterol levels, particularly at the molecular level, have not been clearly elucidated. The objective of the present study was to determine whether different plant sterol analogues reduce plasma cholesterol levels by up regulating the sterol transporters ABCG5 and ABCG8 in the liver and/or small intestine. Male Golden Syrian hamsters were divided into eight groups. Groups 1 and 2 were fed a maize starch–casein–sucrose-based diet that did not contain cholesterol (control; Con) or the Con diet with the addition of 0·25 % cholesterol (Ch-Con). Groups 3–8 were fed the Ch-Con diet supplemented with 1 % plant sterols, 1 % plant stanols, 1 % of a plant sterol and stanol mixture (50:50), 1·76 % plant sterol–fish oil esters, or 0·71 or 1·43 % stanol–ascorbic acid esters, respectively. After 5 weeks, the Ch-Con diet up regulated the ABCG5 mRNA expression and tended (P = 0·083) to increase ABCG8 mRNA expression in the liver, but did not affect both genes’ expression in the small intestine compared with the Con diet. Hamsters fed 0·7 % stanol esters showed lower plasma cholesterol levels (P < 0·001) and also lower liver ABCG5 mRNA expression (P < 0·05) compared with the Ch-Con diet. Plant stanols, stanol esters, and sterol esters did not affect the ABCG5 or ABCG8 mRNA expressions in the liver and intestine although they reduced plasma cholesterol levels. These results suggest that plant sterols and their derivatives reduce plasma cholesterol levels independently from the mRNA expression of ABCG5 and ABCG8 transporters.

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Metabolic and genetic factors modulating subject specific LDL-C responses to plant sterol therapy1This article is an invited review for the Journal's Made In Canada section. The authors gratefully acknowledge the training that was acquired at the Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba. We would specifically like to thank Dr. Peter Jones for his mentorship and significant contribution to the research contained within this manuscript.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-060 ◽

2012 ◽

Vol 90 (5) ◽

pp. 509-514 ◽

Cited By ~ 15

Author(s):

Todd C. Rideout ◽

Scott V. Harding ◽

Dylan S. Mackay

Keyword(s):

Plant Sterol ◽

Disease Risk ◽

Current Knowledge ◽

Cardiovascular Disease Risk ◽

Cholesterol Absorption ◽

Plant Sterols ◽

Lipid Lowering ◽

Clear Understanding ◽

Significant Heterogeneity ◽

Intestinal Cholesterol Absorption

Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption.

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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]

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

Nutrients ◽

10.3390/nu11020310 ◽

2019 ◽

Vol 11 (2) ◽

pp. 310 ◽

Cited By ~ 8

Author(s):

Takanari Nakano ◽

Ikuo Inoue ◽

Takayuki Murakoshi

Keyword(s):

Cholesterol Efflux ◽

Plant Sterol ◽

De Novo ◽

Surrogate Marker ◽

Inverse Correlation ◽

Cholesterol Absorption ◽

Absorption Efficiency ◽

Cholesterol Homeostasis ◽

Paired Data ◽

Intestinal Cholesterol Absorption

Cholesterol homeostasis is maintained through a balance of de novo synthesis, intestinal absorption, and excretion from the gut. The small intestine contributes to cholesterol homeostasis by absorbing and excreting it, the latter of which is referred to as trans-intestinal cholesterol efflux (TICE). Because the excretion efficiency of endogenous cholesterol is inversely associated with the development of atherosclerosis, TICE provides an attractive therapeutic target. Thus, elucidation of the mechanism is warranted. We have shown that intestinal cholesterol absorption and TICE are inversely correlated in intestinal perfusion experiments in mice. In this review, we summarized 28 paired data sets for absorption efficiency and fecal neutral sterol excretion, a surrogate marker of TICE, obtained from 13 available publications in a figure, demonstrating the inverse correlation were nearly consistent with the assumption. We then offer a bidirectional flux model that accommodates absorption and TICE occurring in the same segment. In this model, the brush border membrane (BBM) of intestinal epithelial cells stands as the dividing ridge for cholesterol fluxes, making the opposite fluxes competitive and being coordinated by shared BBM-localized transporters, ATP-binding cassette G5/G8 and Niemann-Pick C1-like 1. Furthermore, the idea is applied to address how excess plant sterol/stanol (PS) intake reduces circulating cholesterol level, because the mechanism is still unclear. We propose that unabsorbable PS repeatedly shuttles between the BBM and lumen and promotes concomitant cholesterol efflux. Additionally, PSs, which are chemically analogous to cholesterol, may disturb the trafficking machineries that transport cholesterol to the cell interior.

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Low Levels of Viscous Hydrocolloids Lower Plasma Cholesterol in Rats Primarily by Impairing Cholesterol Absorption

Journal of Nutrition ◽

10.1093/jn/130.2.243 ◽

2000 ◽

Vol 130 (2) ◽

pp. 243-248 ◽

Cited By ~ 48

Author(s):

Marie-Anne Levrat-Verny ◽

Stephen Behr ◽

Vikkie Mustad ◽

Christian Rémésy ◽

Christian Demigné

Keyword(s):

Plasma Cholesterol ◽

Cholesterol Absorption ◽

Lower Plasma ◽

Lower Plasma Cholesterol ◽

Low Levels

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Intestinal cholesterol absorption: identification of different binding proteins for cholesterol and cholesterol absorption inhibitors in the enterocyte brush border membrane

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/s1388-1981(03)00068-4 ◽

2003 ◽

Vol 1633 (1) ◽

pp. 13-26 ◽

Cited By ~ 24

Author(s):

Werner Kramer ◽

Frank Girbig ◽

Daniel Corsiero ◽

Katja Burger ◽

Falk Fahrenholz ◽

...

Keyword(s):

Brush Border ◽

Binding Proteins ◽

Brush Border Membrane ◽

Cholesterol Absorption ◽

Intestinal Cholesterol Absorption

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A role for NPC1 and NPC2 in intestinal cholesterol absorption – the hypothesis gutted

Biochemical Journal ◽

10.1042/bj20071340 ◽

2007 ◽

Vol 408 (1) ◽

Cited By ~ 5

Author(s):

Laura Liscum

Keyword(s):

Endoplasmic Reticulum ◽

Dietary Cholesterol ◽

Cholesterol Absorption ◽

Cholesterol Transport ◽

Intestinal Epithelial ◽

Intestinal Cholesterol Absorption ◽

Biochemical Journal ◽

Good Target ◽

Type C ◽

Niemann Pick

Dietary and biliary cholesterol are taken up by intestinal epithelial cells and transported to the endoplasmic reticulum. At the endoplasmic reticulum, cholesterol is esterified, packaged into chylomicrons and secreted into the lymph for delivery to the bloodstream. NPC1L1 (Niemann–Pick C1-like 1) is a protein on the enterocyte brush-border membrane that facilitates cholesterol absorption. Cholesterol's itinerary as it moves to the endoplasmic reticulum is unknown, as is the identity of any cellular proteins that facilitate the movement. Two proteins that play an important role in intracellular cholesterol transport and could potentially influence NPC1L1-mediated cholesterol uptake are NPC1 and NPC2 (Niemann–Pick type C disease proteins 1 and 2). In this issue of the Biochemical Journal, Dixit and colleagues show that the absence or presence of NPC1 and NPC2 has no effect on intestinal cholesterol absorption in the mouse. Thus neither protein fills the gap in our knowledge of intra-enterocyte cholesterol transport. Furthermore, the NPC1/NPC2 pathway would not be a good target for limiting the uptake of dietary cholesterol.

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The effect of plant stanol- and sterol-enriched foods on lipid metabolism, serum lipids and coronary heart disease

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/0004563054255605 ◽

2005 ◽

Vol 42 (4) ◽

pp. 254-263 ◽

Cited By ~ 41

Author(s):

Helena Gylling ◽

Tatu A Miettinen

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Serum Cholesterol ◽

Plant Sterol ◽

Plant Sterols ◽

Intestinal Cholesterol Absorption ◽

Sterol Esters ◽

Cholesterol Lowering ◽

Plant Stanol ◽

Plant Stanol Esters

Phytosterols are plant sterols, mainly campesterol and sitosterol, and their respective stanols (5α-saturated derivatives), which chemically resemble cholesterol. They are present in a normal diet and are absorbed proportionally to cholesterol, but to a much lesser extent, such that less than 0.1% of serum sterols are plant sterols. Phytosterols inhibit intestinal cholesterol absorption, and fat-soluble plant stanol esters were introduced as a functional food for lowering serum cholesterol in the early 1990s; plant sterol esters entered the market at the end of the 1990s. Inhibition of the intestinal absorption of cholesterol stimulates cholesterol synthesis, a factor which limits serum cholesterol lowering to about 10% with phytosterols. Enrichment of the diet with plant stanol esters reduces absorption and serum concentrations of both cholesterol and plant sterols, whereas enrichment of the diet with plant sterol esters, especially in combination with statins, lowers serum cholesterol but increases serum plant sterol levels. Recent studies have suggested that high-serum plant sterol levels may be associated with increased coincidence of coronary heart disease. Estimates of coronary heart disease reduction by 20-25% with plant sterols/stanols is based mainly on short-term studies. Long-term cholesterol lowering, needed for the prevention of coronary heart disease, may be successful with plant stanol esters, which lower serum cholesterol in both genders over at least a year.

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