Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study

Abstract

The major oxysterols in human circulation are 7 ␣ -, 27-, and (24 S )-hydroxycholesterol. Two unique experiments were performed to elucidate their origin and kinetics. A volunteer was exposed to 18 O 2 -enriched air. A rapid incorporation of 18 O in both 7 ␣ -and 27-hydroxycholesterol and disappearance of label after exposure were observed. The half-life was estimated to be less than 1 h. Incorporation of 18 O in (24 S )-hydroxycholesterol was not significant. In the second experiment a volunteer was infused with liposomes containing 10 g of [ 2 H 6 ]cholesterol. This resulted in an enrichment of plasma cholesterol with 2 H of up to 13%, and less than 0.5% in cerebrospinal fluid cholesterol. The content of 2 H in circulating 7 ␣ -hydroxycholesterol remained approximately equal to that of plasma cholesterol and decreased with a half-life of about 13 days. The 2 H content of circulating 27-hydroxycholesterol was initially lower than that of cholesterol but in the last phase of the experiment it exceeded that of cholesterol. No significant incorporation of 2 H in (24 S )-hydroxycholesterol was observed. It is evident that 7 ␣ -hydroxycholesterol must originate from a rapidly miscible pool, about 80% of 27-hydroxycholesterol from a more slowly exchangeable pool, and more than 90% of (24 S )-hydroxycholesterol from a nonexchangeable pool, presumably the brain. The results are discussed in relation to the role of oxysterols in cholesterol homeostasis and their use as markers for pathological conditions. -Meaney,

Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon?

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“…To be excreted from the brain, cholesterol is converted into 24S-hydroxycholesterol (24S-OHC), a molecule that dynamically crosses the BBB and reaches peripheral circulation, being eliminated in biliary acids [10]. This conversion is mediated by a key enzyme of brain cholesterol metabolism, termed cholesterol 24-hydroxylase (CYP46A1), a member of the cytochrome P450 family [41] mainly expressed in neurons [35]. CYP46A1 has been shown to play a major role in the turnover of brain cholesterol and in neuronal responses to stress [10,66].…”

New Function of Cholesterol Oxidation Products Involved in Osteoporosis Pathogenesis

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