The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates bile acid biosynthesis.
Fibrates are a group of hypolipidemic agents that efficiently lower serum triglyceride levels by affecting the expression of many genes involved in lipid metabolism. These effects are exerted via the peroxisome proliferator-activated receptor alpha (PPARalpha). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPARalpha and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12alpha-hydroxylase is a branch-point enzyme in the bile acid biosynthetic pathway, which determines the ratio of cholic acid to chenodeoxycholic acid. Treatment of mice for 1 week with the peroxisome proliferator WY-14,643 or fasting for 24 h both induced the sterol 12alpha-hydroxylase mRNA in liver. Using the PPARalpha knockout mouse model, we show that the induction by both treatments was dependent on the PPARalpha. A reporter plasmid containing a putative peroxisome proliferator-response element (PPRE) identified in the rat sterol 12alpha-hydroxylase promoter region was activated by treatment with WY-14,643 in HepG2 cells, being dependent on co-transfection with a PPARalpha expression plasmid. The rat 12alpha-hydroxylase PPRE bound in vitro translated PPARalpha and retinoid X receptor alpha, albeit weakly, in electrophoretic mobility shift assay. Treatment of wild-type mice with WY-14,643 for 1 week resulted in an increased relative amount of cholic acid, an effect that was abolished in the PPARalpha null mice, verifying the functionality of the PPRE in vivo.
Hunt
M C
MC
Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, S-141 86 Stockholm, Sweden.
Yang
Y Z
YZ
Eggertsen
G
G
Carneheim
C M
CM
Gåfvels
M
M
Einarsson
C
C
Alexson
S E
SE
D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology; D020218:Response Elements; D047488:Retinoid X Receptors; D013253:Steroid 12-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*
D001647:Bile Acids and Salts; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D013253:Steroid 12-alpha-Hydroxylase