Clofibrate, a peroxisome-proliferator, enhances reverse cholesterol transport through cytochrome P450 activation and oxysterol generation.
Fibrates are widely used hypolipidemic agents that activate the peroxisome proliferator-activated receptor a (PPARalpha) and regulate the expression of many genes involved in lipid metabolism. We studied the mechanism of the effect of clofibrate on cholesterol homeostasis. Rats were fed with chow containing clofibrate, cytochrome P-450 inhibitor ketoconazole, or clofibrate plus ketoconazole. Control rats were fed only with normal chow. The levels of six oxysterols in liver microsome were determined. The levels of mRNAs for liver X receptor alpha (LXRalpha), ATP-binding cassette A1 (ABCA1), PPARalpha and cholesterol 7alpha-hydroxylase (CYP7A) in the liver were analyzed by northern blotting. Clofibrate administration decreased plasma levels of total cholesterol and triglyceride and increased high-density lipoprotein-cholesterol (HDL-C). Clofibrate increased the levels of liver microsomal oxysterols including 25- and 27-hydroxycholesterol, which are potent activators of LXRalpha. Clofibrate also enhanced the expression of mRNAs for PPARalpha, LXRalpha, and ABCA1. Simultaneous administration of ketoconazole suppressed the effects of clofibrate on plasma lipids, hepatic oxysterol levels, and the expression of the genes. Clofibrate increases cytochrome P450 content and the resulting oxysterol generation may partly mediate the clofibrate-induced up-regulattion of LXRa and ABCA1, which are related to reverse cholesterol transport.
Guan
Jing-Zhi
JZ
Third Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan.
Tamasawa
Naoki
N
Murakami
Hiroshi
H
Matsui
Jun
J
Yamato
Kazumi
K
Suda
Toshihiro
T
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001692:Biological Transport; D015152:Blotting, Northern; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004359:Drug Therapy, Combination; D006888:Hydroxycholesterols / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D020025:Peroxisome Proliferators / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D020025:Peroxisome Proliferators; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D014157:Transcription Factors; D012313:RNA; C076996:27-hydroxycholesterol; C007997:25-hydroxycholesterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D002994:Clofibrate; D007654:Ketoconazole