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Journal of Lipid Research, Vol. 44, 2049-2058, November 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

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

Brian L. Knight^1,*, Dilip D. Patel^*, Sandy M. Humphreys, David Wiggins and Geoffrey F. Gibbons

^* Lipoprotein Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 ONN, UK
Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK

¹ To whom correspondence should be addressed. e-mail: brian.knight{at}csc.mrc.ac.uk

Dietary supplementation with the peroxisome proliferator-activated receptor (PPAR) 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 PPAR-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 cholesterol, 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 mRNA encoding the sterol-regulatory element binding protein-1c gene (SREBP-1c), a known target gene for the oxysterol receptor liver X receptor (LXR). 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 PPAR influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXR.

Supplementary key words intestine • sterol-regulatory element binding protein • liver X receptor • peroxisome proliferator-activated receptor- null mice • -3 unsaturated fatty acid

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