Rapid hepatic metabolism of 7-ketocholesterol in vivo: implications for dietary oxysterols

Abstract

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 [14C]-7-ketocholesterol and [3H]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, 14C 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, 14C 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 3H was evident in the liver while only 5% was found in the intestine. Unlike [3H]cholesterol, little 14C 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 [14C]-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., S. Samman, L. Gatto, and A. J. Brown. Rapid hepatic metabolism of 7-ketocholesterol in vivo: implications for dietary oxysterols. J. Lipid Res. 1999. 40: 1846–1857

Keywords

• oxysterol
• cholesterol oxidation
• 7-oxocholesterol
• rat