The effect of oxidizing cholesterol on gastrointestinal absorption, plasma clearance, tissue distribution, and processing by endothelial cells.
Little is known about the absorption or metabolism of oxysterols. Toward better appreciating the metabolic consequences of oxidizing cholesterol, we compared labeled cholesterol with the labeled oxysterols 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, and 7-ketocholesterol prepared from [4-14C]cholesterol, [26,26,26,27,27,27-2H6]cholesterol, and [23,24,25,26,27-13C5] cholesterol. Gastrointestinal absorption of oxysterols in rats was 91.5 +/- 0.3% compared with 75 +/- 1.1% for cholesterol, determined by fecal collection (P < .001). When injected intravenously and followed by gas chromatography/mass spectrometry, 7 alpha-hydroxycholesterol was cleared at 23 times the rate of cholesterol. After 5 minutes, only 1.2 +/- 0.2% of 7 alpha-hydroxycholesterol remained in the plasma, whereas 28.0 +/- 1.7% of cholesterol and 40.0 +/- 2.5% of a triglyceride emulsion injected simultaneously were still present. [14C]7 alpha-Hydroxycholesterol injected intravenously was also rapidly cleared from plasma, was widely distributed in tissues and organs, and showed evidence of extensive metabolism at 5 minutes. The fractional rate of uptake of radiolabeled oxysterols by cultured endothelial cells was 15.7 times that of cholesterol (P < .001), and the fractional rate of efflux was 3.4 times that of cholesterol (P < .001). Oxysterols passed through endothelial cells grown on transwell membranes at a rate 4.3 times that of cholesterol (P < .001). Fractional oxysterol transport across the endothelial cell monolayer was increased 62 +/- 17% when HDL was added to the medium in the lower chamber (P = .003). Oxysterols were extensively metabolized to even more polar metabolites during endothelial cell transit. These properties of oxysterols potentially provide a mechanism for enhancing transport of cholesterol through tissues and preventing accumulation of cholesterol in those cells that can oxidize it.
Krut
L H
LH
Metabolism Division, Washington University School of Medicine, St Louis, MO, USA.
Yang
J W
JW
Schonfeld
G
G
Ostlund
R E
RE
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D006888:Hydroxycholesterols / Q000378:metabolism*; D007408:Intestinal Absorption; D007653:Ketocholesterols / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010084:Oxidation-Reduction; D051381:Rats; D014018:Tissue Distribution
D006888:Hydroxycholesterols; D007653:Ketocholesterols; C011724:cholest-5-en-3 beta,7 alpha-diol; D002784:Cholesterol; C003001:7-ketocholesterol