Intestinal Absorption of γ-Tocotrienol Is Mediated by Niemann-Pick C1-Like 1: In Situ Rat Intestinal Perfusion Studies

Abuasal, Bilal; Sylvester, Paul W.; Kaddoumi, Amal

doi:10.1124/dmd.109.031567

Cited by 57 publications

(71 citation statements)

References 39 publications

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“…5,14) Abuasal et al reported that the intestinal absorption of γ-tocotrienol is partly mediated by NPC1L1. 23) We also reported that NPC1L1 is partly involved in the absorption of lutein, a dihydroxycarotenoid. 6) As just described, it was suggested that some components that do not have a sterol structure are substrates of NPC1L1.…”

Section: Effect Of Cholesterol In Lipid Emulsion Particles On the Uptmentioning

confidence: 99%

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components <i>via</i> Niemann–Pick C1-Like 1

Takekawa

Sato

Yamaki

et al. 2016

Biological & Pharmaceutical Bulletin

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Dietary and biliary cholesterol absorption contributes to the maintenance of tight control of cholesterol homeostasis. Cholesterol is present as mixed micelles formed by bile salts and phospholipids in the intestinal lumen. Recently, Niemann-Pick C1-Like 1 (NPC1L1) transporter was identified as being critical for cholesterol absorption. However, the uptake mechanism of an enveloped substrate of NPC1L1 in whole lipid emulsion particles remains unclear. In this study, we investigated the uptake mechanism of a substrate of NPC1L1 in lipid emulsion particles. We also investigated whether these particles containing cholesterol can improve the intestinal absorption of other lipophilic components via NPC1L1. The uptake of lysophosphatidylcholine (LPC)-4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-propionic acid saccinimidyl ester (BODIPY), a fluorescently labeled phospholipid, in lipid emulsion particles containing cholesterol (1 µM) was significantly increased compared to that without cholesterol in Caco-2 cells. On the other hand, its increased uptake was significantly inhibited by ezetimibe, a selective inhibitor of NPC1L1. These results suggested that not only cholesterol but also some components in lipid emulsion particles are taken up into enterocytes via NPC1L1. We also examined an approach to improve intestinal absorption of a poorly absorbed water-insoluble component, coenzyme Q10 (CoQ10), by this mechanism. The uptake of CoQ10 in lipid emulsion particles containing cholesterol was significantly increased compared to that without cholesterol. Its increased uptake was significantly inhibited by ezetimibe. Though it is still not clear whether CoQ10 is a substrate of NPC1L1, there is a potential for improvement of the absorption of poorly absorbed components by lipid emulsion particles containing cholesterol.Key words Niemann-Pick C1-Like 1; absorption; cholesterol; emulsion; coenzyme Q10Intestinal absorption is an important process in the maintenance of homeostasis in the body. Cholesterol homeostasis is a highly regulated balance of de novo synthesis, dietary cholesterol absorption, and biliary clearance and excretion. Although the cholesterol uptake mechanism in the intestinal lumen is not fully understood, the identification of ezetimibe as a selective inhibitor of intestinal cholesterol absorption suggested that these processes are mediated by a specific transport system rather than by passive diffusion.1) In 2004, Altmann et al. identified Niemann-Pick C1-Like 1 (NPC1L1) as an apically localized sterol transporter in the small intestine.2) NPC1L1 is highly expressed in the small intestine, particularly in the upper intestine.2,3) NPC1L1 protein has 13 predicted transmembrane domains and extensive N-linked glycosylation sites located within the extracellular loops and it contains a sterol sensing domain (SSD).4) It has predicted that the substrates of NPC1L1 have sterol domains and have been mainly thought to transport the substance involving the sterol structure.Cholesterol is pre...

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Section: Effect Of Cholesterol In Lipid Emulsion Particles On the Uptmentioning

confidence: 99%

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components <i>via</i> Niemann–Pick C1-Like 1

Takekawa

Sato

Yamaki

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Liver microsomes from different species such as human, mouse, rat, dog and monkey were used in the study to see the variations of activity. Results indicated that 20S(OH)D 3 and 20R(OH)D 3 both have good metabolic stability irrespective of variations between them against multi species microsomes. The half-life for 20S(OH)D 3 was 50 min, and 20R(OH)D 3 was just 30 min.…”

Section: Vitamin D Analogsmentioning

confidence: 97%

“…Other than toxicity studies, anti-proliferative studies showed similar or higher effect of analogs compared to their parent compounds. Analogs, 20S(OH)D 3 and 20R(OH)D 3 , also translocated the vitamin D receptor (VDR) to the nucleus from cytoplasm which can be effective to make gene regulation mediated anti-proliferative activity [32].…”

Section: Vitamin D Analogsmentioning

confidence: 99%

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Enhanced Bioavailability and Anticancer Activity of Vitamin Analogs

Pr¹,

Kln²

2017

J Bioequiv Availab

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“…Studies are also being conducted to advantage of alternative formulation (Figure 3) types to enhance bioavailability of the drugs [17][18][19]. Studies were conducted to compare the oral bioavailability of tocopherols and tocotrienols when administered in vivo in form of oil solutions [20,21]. These studies also made insights into the intestinal solubilization and permeability of the same.…”

Section: Introductionmentioning

confidence: 99%

A Brief Journey of Tocotrienols as Anticancer Agents

Kabir¹,

Rahman²,

Rahman³

et al. 2017

J In Silico In Vitro Pharmacol

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The journey of tocotrienol is started when the Vitamin E was first discovered as the fertility factor. Later in the research studies vitamin E was found to be consisting of eight isomers which can be divided into two separate groups known as tocopherols and tocotrienols. The isomers share similarity in structure but differ at much levels based upon their functional or biological properties. Initially tocopherols were investigated much due to their powerful antioxidant properties. However, the other four isomers of tocotrienols were found to be consisting of anticancer properties at varying degree in vitro and in vivo. The mechanisms mediated by tocotrienols such as NFkB pathway, apoptosis, and effect on DNA polymerases are totally different to those of tocopherols.

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Intestinal Absorption of γ-Tocotrienol Is Mediated by Niemann-Pick C1-Like 1: In Situ Rat Intestinal Perfusion Studies

Cited by 57 publications

References 39 publications

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components <i>via</i> Niemann–Pick C1-Like 1

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components <i>via</i> Niemann–Pick C1-Like 1

Enhanced Bioavailability and Anticancer Activity of Vitamin Analogs

A Brief Journey of Tocotrienols as Anticancer Agents

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