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A more recent version of this article appeared on November 1, 2003

Papers In Press, published online ahead of print August 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300042-JLR200
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Submitted on January 28, 2003
Revised on July 24, 2003
Accepted on July 25, 2003

Inhibition of cholesterol absorption associated with a PPAR-alpha -dependent increase in ABC transporter A1 in mice

Brian L. Knight, Dilip D. Patel, Sandy M. Humphreys, David Wiggins, and Geoffrey F. Gibbons

Lipoprotein Group, Faculty of Medicine, MRC Clincal Sciences Centre, Imperial College, London W12 ONN

Corresponding Author: brian.knight{at}csc.mrc.ac.uk

Dietary supplementation with the peroxisome proliferator-activated receptor-alpha (PPARalpha ) ligand WY 14,643 gave rise to a 4 to 5-fold increase in the expression of mRNA for the ATP-binding cassette transporter A1 (ABCA1) in the intestine of normal mice. There was no effect in the intestine of PPARalpha -null mice. Consumption of a high cholesterol diet also increased intestinal ABCA1 expression. The effects of WY 14,643 and the high cholesterol diet were not additive. WY 14,643 feeding reduced intestinal absorption of cholesterol in the normal mice, irrespective of the dietary cholesterol concentration, and this resulted in lower diet-derived cholesterol and cholesteryl ester concentrations in plasma and liver. At each concentration of dietary cholester ol there was a similar significant inverse correlation between intestinal ABCA1 mRNA content and the amount of cholesterol absorbed. The fibrate-induced changes in the intestines of the normal mice were accompanied by an increased concentration of the mR NA encoding SREBP-1c, a known target gene for the oxysterol receptor LXRalpha . There was a correlation between intestinal ABCA1 mRNA and SREBP-1c mRNA contents, but not between SREBP-1c mRNA content and cholesterol absorption. These results suggest that PPARalpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXRalpha .


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