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 (PPAR alpha) 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 alpha-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 (LXR alpha). 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 alpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXR alpha.
Knight
Brian L
BL
Lipoprotein Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 ONN, UK. brian.knight@csc.mrc.ac.uk
Patel
Dilip D
DD
Humphreys
Sandy M
SM
Wiggins
David
D
Gibbons
Geoffrey F
GF
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000042:Absorption / Q000187:drug effects; D000821:Animal Feed; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D019587:Dietary Supplements; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D022762:CCAAT-Enhancer-Binding Proteins; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C006253:pirinixic acid; D002784:Cholesterol