Rapid hepatic metabolism of 7-ketocholesterol in vivo: implications for dietary oxysterols.
7-Ketocholesterol is a major dietary oxysterol and the predominant non-enzymically formed oxysterol in human atherosclerotic plaque. We tested the hypothesis that 7-ketocholesterol is preferentially retained by tissues relative to cholesterol in vivo. To ensure rapid tissue uptake, acetylated low density lipoprotein, labeled with esters of [(14)C]-7-ketocholesterol and [(3)H]cholesterol, was injected into rats via a jugular catheter. At timed intervals (2 min to 24 h) rats (n = 48 total) were exsanguinated and tissues were dissected and assayed for radioactivity. In two experiments the majority of both radiolabels appeared in the liver after 2 min. In all tissues, (14)C appeared transiently and did not accumulate. Rather, it was metabolized in the liver and excreted into the intestine mainly as aqueous-soluble metabolites (presumably bile acids). By 9 h, (14)C in the liver had decreased to 10% of the injected dose while 36% was present in the intestine. In contrast, at 9 h 38% of (3)H was evident in the liver while only 5% was found in the intestine. Unlike [(3)H]cholesterol, little (14)C was found to re-enter the circulation, indicating that enterohepatic recycling of 7-ketocholesterol was negligible. This is the first report of the distribution of an oxysterol relative to cholesterol, administered simultaneously, in a whole animal model. The finding that [(14)C]-7-ketocholesterol is rapidly metabolized and excreted by the liver suggests that diet may not be a major source of oxysterols in atherosclerotic plaque, and that perhaps dietary oxysterols make little or no contribution to atherogenesis.
Lyons
M A
MA
Cell Biology Group, Heart Research Institute, Camperdown, New South Wales, 2050, Australia.
Samman
S
S
Gatto
L
L
Brown
A J
AJ
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002250:Carbon Radioisotopes; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007653:Ketocholesterols / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D011865:Radioisotope Dilution Technique; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012588:Scintillation Counting; D013261:Sterols / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D001647:Bile Acids and Salts; D002250:Carbon Radioisotopes; D004041:Dietary Fats; D007653:Ketocholesterols; D013261:Sterols; D002784:Cholesterol; C003001:7-ketocholesterol