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

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 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 alpha (LXRalpha). There was a correlation between intestinal ABCA1 mRNA and SRFBP-1c mRNA contents, but not between SFEBP-1c mRNA content and cholesterol absorption.jlr These results suggest that PPARalpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXRalpha.-Knight, B. L., D. D. Patel, S. M. Humphreys, D. Wiggins, and G. E Gibbons. Inhibition of cholesterol absorption associated with a PPARalpha-dependent increase in ABC binding cassette transporter Al in mice.