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1 Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: walrefai{at}uic.edu.
Bile acids are efficiently absorbed from the intestinal lumen via the ileal Apical Sodium-Dependent Bile Acid Transporter (ASBT). ASBT function is essential for maintenance of cholesterol homeostasis in the body. The molecular mechanisms of the direct effect of cholesterol on human ASBT function and expression are not entirely understood. The present studies were undertaken to establish a suitable in vitro experimental model to study human ASBT function and its regulation by cholesterol. Luminal membrane bile acid transport was evaluated by the measurement of sodiumdependent 3H-taurocholic (TC) uptake in human intestinal Caco2 cell monolayers. The relative abundance of hASBT mRNA was determined by real time PCR. Transient transfection and luciferase assay techniques were employed to assess hASBT promoter activity. Caco2 cell line was found to represent a suitable model to study hASBT function and regulation. 25-hydroxycholesterol (25-HCH, 2.5 µg/ml for 24h) significantly inhibited Na+-dependent 3H-TC uptake in Caco2 cells. This inhibition was associated with a 50 % decrease in the Vmax of the transporter with no significant changes in the apparent Km. The inhibition in hASBT activity was associated with reduction in both the level of hASBT mRNA and its promoter activity. Our data show the inhibition of hASBT function and expression by 25-hydroxycholesterol in Caco2 cells. These data provide novel evidence for the direct regulation of human ASBT function by cholesterol and suggest that this phenomenon may play a central role in cholesterol homeostasis.
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