The Effect of Oxidizing Cholesterol on Gastrointestinal Absorption, Plasma Clearance, Tissue Distribution, and Processing by Endothelial Cells

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Abstract
Abstract 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 7α-hydroxycholesterol, 7β-hydroxycholesterol, and 7-ketocholesterol prepared from [4- 14 C]cholesterol, [26,26,26,27,27,27- 2 H 6 ]cholesterol, and [23,24,25,26,27- 13 C 5 ]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, 7α-hydroxycholesterol was cleared at 23 times the rate of cholesterol. After 5 minutes, only 1.2±0.2% of 7α-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. [ 14 C]7α-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.