NPC1L1 inhibition disturbs lipid trafficking and induces large lipid droplet formation in intestinal absorptive epithelial cells

BioRxiv : the Preprint Server for Biology
Takanari NakanoT. Murakoshi


Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein, which mediates intracellular cholesterol trafficking from the brush border membrane to the endoplasmic reticulum, where chylomicron assembly takes place in enterocytes or in the intestinal absorptive epithelial cells. Cholesterol is a minor lipid component of chylomicrons; however, whether or not a shortage of cholesterol attenuates chylomicron assembly is unknown. The aim of this study was to examine the effect of NPC1L1 inhibition on trans-epithelial lipid transport, and chylomicron assembly and secretion in enterocytes. Caco-2 cells, an absorptive epithelial model, grown onto culture inserts were given lipid micelles from the apical side, and chylomicron-like triacylglycerol-rich lipoprotein secreted basolaterally were analyzed after a 24-h incubation period in the presence of ezetimibe up to 50 M. The secretion of lipoprotein and apolipoprotein B48 were reduced by adding ezetimibe (30%, p<0.01 and 34%, p<0.05, respectively). Additionally, ezetimibe accelerated intracellular apoB protein degradation by approximately 2.8-fold and activated sterol regulatory element binding protein 2 by approximately 1.5-fold: These are indicators whether the cells are sensing cellula...Continue Reading

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