Respective contributions of intestinal Niemann-Pick C1-like 1 and scavenger receptor class B type I to cholesterol and tocopherol uptake:in vivov.in vitrostudies

Abstract

The intestinal absorption of cholesterol and lipid micronutrients such as vitamin E has been shown to share some common pathways. The present study aims to further compare the uptake of cholesterol ([ 3 H]cholesterol v. 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3-ol (NBD-cholesterol)) and tocopherol in Caco-2 TC-7 cells and in mouse intestine, with special focus on the respective roles of scavenger receptor class B type I (SR-BI) and Niemann-Pick C1-like 1 (NPC1L1). Conversely to NBD-cholesterol, the uptakes of [ 3 H]cholesterol and tocopherol by Caco-2 cells were impaired by both block lipid transport-1 and ezetimibe, which inhibit SR-BI and NPC1L1, respectively. These inhibitions occurred only when cholesterol or tocopherol was delivered to cells included in micelles that contained biliary acid and at least oleic acid as a lipid. In vivo, after 2 h of digestion in mice, the uptake of the two cholesterol analogues and of tocopherol all showed distinct patterns along the duodenum-jejunum axis. [ 3 H]Cholesterol uptake, which correlated closely to NPC1L1 mRNA expression in wild-type (wt) mice, was strongly inhibited by ezetimibe. Intestinal SR-BI overexpression did not change NPC1L1 expression and led to a significant increase in [ 3 H]cholesterol uptake in the distal jejunum. Conversely, neither ezetimibe treatment nor SR-BI overexpression had an effect on NBD-cholesterol uptake. However, in contrast with SR-BI mRNA expression, tocopherol absorption increased strongly up to the distal jejunum in wt mice where it was specifically inhibited by ezetimibe, and was increased in the proximal intestine of intestinal SR-BI-overexpressing mice. Thus, cholesterol and tocopherol uptakes share common pathways in cell culture models, but display different in vivo absorption patterns associated with distinct contributions of SR-BI and NPC1L1.

Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops

“…Moreover, accordingly to our SPR data showing that free OA and DHA were SR-BI ligands, mice overexpressing SR-BI at the A key fi nding is that these structures mimicking mixed micelles, i.e., including various lipids and lipid digestion products, are necessary for optimal binding to both lCD36 and lSR-BI. This is consistent with previous results showing that SR-BI could bind postprandial but not interprandial micelles ( 13 ), and that cholesterol uptake from simple micelles was unaffected by the addition of SR-BI inhibitor, in contrast to cholesterol uptake from mixed micelles ( 34 ).…”

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

“…On the other hand, Chol-NBD (22-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino)-23,24-bisnor-5-cholen-3β-ol) is reported to be absorbed via NPC1L1-independent pathway. 16,17) In terms of cholesterol uptake via NPC1L1, it has been reported that the N-terminal domain of NPC1L1 binds cholesterol and promotes formation of cholesterol-enriched membrane microdomains comprising lipid raft proteins flotillin-1 and flotillin-2. 8,18) Clathrin is then recruited to internalize the NPC1L1-flotillin-cholesterol membrane microdomains.…”

“…We also consider that further studies are needed to clarify the recognition of cholesterol and its related-substances, substrates of NPC1L1, as Reboul et al also suggested that the chemical modification from cholesterol to NBD-Chol has a real impact in NPC1L1 recognition. 17) We then investigated how lipid emulsion particles themselves were incorporated into Caco-2 cells as well as cholesterol (Fig. 3).…”

Mechanisms for the prevention of vitamin E excess

“…Apparently, cystic fi brosis impedes vitamin E absorption only in those individuals with impaired bile secretion, suggesting that the requirement for gastrointestinal lipase is not as great as that for bile acids ( 25,26 ). The minimum requirements for vitamin E absorption have been reported as its incorporation into micelles containing taurocholate and oleic acid ( 27 ). It is unclear whether these components function to solubilize vitamin E for its uptake into enterocytes or whether they function as ligands for specifi c receptors for internalization of the micelle.…”

“…Additionally, the scavenger receptor B-1 (SR B-1) has been shown to facilitate both cholesterol and tocopherol uptake into enterocytes and to be inhibited by a specifi c SR B-1 inhibitor, block lipid transport-1 (BLT-1) ( 27,29 ). However, when evaluated in vivo, cholesterol and tocopherol absorption by mice occurred in quite different locations, with the greatest tocopherol absorption in the distal jejunum, suggesting there may be additional mechanisms/receptors/transporters involved in vitamin E absorption ( 27 ).…”