Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men.
OBJECTIVE
The objective of this work was to explore the role of peroxisome proliferator-activated receptor delta (PPARD) in lipid metabolism in humans.


RESULTS
PPARD is a nuclear receptor involved in lipid metabolism in primates and mice. We screened the 5'-region of the human gene for polymorphisms to be used as tools in association studies. Four polymorphisms were detected: -409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%, respectively, in a population-based group of 543 healthy men. Only the +294T/C polymorphism showed significant association with a metabolic trait. Homozygotes for the rare C allele had a higher plasma LDL-cholesterol concentration than homozygotes for the common T allele, which was verified in an independent cohort consisting of 282 healthy men. Transfection studies showed that the rare C allele had higher transcriptional activity than the common T allele. Electrophoretic mobility shift assays demonstrated that the +294T/C polymorphism influenced binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also detected for several lipid parameters.


CONCLUSIONS
These findings suggest that PPARD plays a role in cholesterol metabolism in humans.
Skogsberg
Josefin
J
Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Kannisto
Katja
K
Cassel
Tobias N
TN
Hamsten
Anders
A
Eriksson
Per
P
Ehrenborg
Ewa
E
D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D000483:Alleles; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003001:Cloning, Molecular; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D013548:Sweden; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D020298:U937 Cells
D020121:5' Untranslated Regions; D008078:Cholesterol, LDL; D018160:Receptors, Cytoplasmic and Nuclear; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D002784:Cholesterol