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

Abstract

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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