Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and ...

Oxysterols: modulators of cholesterol metabolism and other processes.

Lipid peroxidation: Physiological levels and dual biological effects

Oxysterols and atherosclerosis

Cholesterol balance is maintained by a series of regulatory pathways that control the acquisition of cholesterol from endogenous and exogenous sources and the elimination of cholesterol, facilitated by its conversion to bile acids. Over the past decade, investigators have discovered that a family of membrane-bound transcription factors, sterol regulatory element-binding proteins (SREBPs), mediate the end-product repression of key enzymes of cholesterol biosynthesis. Recently orphan members of another family of transcription factors, the nuclear hormone receptors, have been found to regulate key pathways in bile acid metabolism, thereby controlling cholesterol elimination. The study of these orphan nuclear receptors suggests their potential as targets for new drug therapies.

The role of orphan nuclear receptors in the regulation of cholesterol homeostasis

We have investigated whether side chain-hydroxylated cholesterol species are important for elimination of cholesterol from the brain. Plasma concentrations of 24-hydroxycholesterol (24-OH-Chol) in the internal jugular vein and the brachial artery in healthy volunteers were consistent with a net flux of this steroid from the brain into the circulation, corresponding to elimination of approximately 4 mg cholesterol during a 24-h period in adults. Results of experiments with rats exposed to 18O2 were also consistent with a flux of 24-OH-Chol from the brain into the circulation. No other oxysterol measured showed a similar behavior as 24-OH-Chol. These results and the finding that the concentration of 24-OH-Chol was 30- to 1500-fold higher in the brain than in any other organ except the adrenals indicate that the major part of 24-OH-Chol present in the circulation originates from the brain. Both the 24-OH-Chol present in the brain and in the circulation were the 24S-stereoisomer. In contrast to other oxysterols, levels of plasma 24-OH-Chol were found to be markedly dependent upon age. The ratio between 24-OH-Chol and cholesterol in plasma was approximately 5 times higher during the first decade of life than during the sixth decade. There was a high correlation between levels of 24-OH-Chol in plasma and cerebrospinal fluid. It is suggested that the flux of 24-OH-Chol from the brain is important for cholesterol homeostasis in this organ.

https://www.pnas.org/content/pnas/93/18/9799.full.pdf

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation

Sterol metabolism--XLVII. Oxidized cholesterol esters in human tissues.

A means of determination of a ctive hydrogen of hydroxyl, carboxyl, sulfhydryl, amino, amido and sulfonamido groups by chemical ionization mass spectrometry using ammonia and trideuterioammonia as reagent gases is described. The method is based on exchange of active hydrogen for deuterium occurring during the chemical ionization process using trideuterioammonia, with comparison of m/z for ammonium adduct [M + NH1]+ and trideuterioammonium adduct [M--nH + nD + ND4]+, or of protonated molecular ion [M + H]+ and deuteronated molecular ion [M--nH + nD + D]+ yielding the number of active hydrogens. Applications have been made to several classes of biologically important compounds.

Active hydrogen by chemical ionization mass spectrometry.

A means of recognition of functional groups in organic molecules using chemical ionization mass spectrometry is described. Mass spectra of 34 C27-steroids using methane, isobutane and ammonia as reagent gases are recorded and correlations with structure proposed. Ammonia chemical ionization spectra are most instructive, generally yielding abundant ions of four types: an ammonium adduct [M+ NH4]+, an ammonia displacement ion [M + NH3 - X]+, a protonated molecular ion [M + H]+ and an elimination ion [M - X]+. Both the [M + H]+ and [M - X]+ ions appear to derive from the ammonium adduct [M + NH4]+, and the ion [M + NH3 - X]+ derives by a nucleophilic displacement of an elimination fragment X by neutral ammonia. Steroid ketones and olefins give predominantly [M + NH4]+ and [M + H]+ ions, whereas alcohols and esters give a three-component pattern of [M + NH4]+, [M + NH3 - X]+ and [M - X]+ ions. Spectra derived using methane or isobutane as reagent gas contain three major ion types: the protonated molecular ion [M + H]+, the hydride abstraction ion [M - H]+ and the elimination ion [M - X]+. Steroid ketones give the [M + H]+ion predominantly; the olefins give both [M + H]+ and [M - X]+ ions. Steroid alcohols give [M + H]+, [M - X]− ions. Recognition by these means of functionality in nonsteroid compounds appears also to be possible.

Yong Yeng Lin

Papers

Sterol metabolism--XLVII. Oxidized cholesterol esters in human tissues.

Active hydrogen by chemical ionization mass spectrometry.

Recognition of functional groups by chemical ionization mass spectrometry

Sterol metabolism XXVIII. Biosynthesis and accumulation of cholest-5-ene-3β, 24-diol (cerebrosterol) in developing rat brain

Hydroxyl ion negative chemical ionization mass spectra of steroids