Role of the apical and basolateral domains of the enterocyte in the regulation of cholesterol transport by a high glucose concentration

Abstract

We have recently shown that a high glucose (HG) concentration raised intestinal cholesterol (CHOL) transport and metabolism in intestinal epithelial cells. The objective of the present work is to determine whether the stimulus for increased CHOL absorption by glucose originates from the apical site (corresponding to the intestinal lumen) or from the basolateral site (related to blood circulation). We tackled this issue by using differentiated Caco-2/15 cells. Only basolateral medium, supplemented with 25 mmol/L glucose, stimulated [(14)C]-CHOL uptake via the up-regulation of the critical CHOL transporter NPC1L1 protein, as confirmed by its specific ezetimibe inhibitor that abolished the rise in glucose-mediated CHOL capture. No significant changes were noted in SR-BI and CD36. Elevated CHOL uptake was associated with an increase in the transcription factors SREBP-2, LXR-β, and ChREBP, along with a fall in RXR-α. Interestingly, although the HG concentration in the apical medium caused modest changes in CHOL processing, its impact was synergetic with that of the basolateral medium. Our results suggest that HG concentration influences positively intestinal CHOL uptake when present in the basolateral medium. In addition, excessive consumption of diets containing high levels of carbohydrates may strengthen intestinal CHOL uptake in metabolic syndrome, thereby contributing to elevated levels of circulating CHOL and, consequently, the risk of developing type 2 diabetes and cardiovascular disease.