Oxysterol research: a brief review

Abstract

In the present study, we discuss the recent developments in oxysterol research. Exciting results have been reported relating to the involvement of oxysterols in the fields of neurodegenerative disease, especially in Huntington's disease, Parkinson's disease and Alzheimer's disease; in signalling and development, in particular, in relation to Hedgehog signalling; and in cancer, with a special focus on (25R)26-hydroxycholesterol. Methods for the measurement of oxysterols, essential for understanding their mechanism of action in vivo, and valuable for diagnosing rare diseases of cholesterol biosynthesis and metabolism are briefly considered.

Keywords: Hedgehog; Huntington's disease; cholesterol; cytochrome p450; metastasis; sterols.

Figure 1.. Structures of cholesterol, some of its precursors and some oxysterols.

Once 7α-hydroxylated, oxysterols become substrates for the enzyme HSD3B7 (3β-hydroxysteroid dehydrogenase type 7) and can be converted from their 3β-hydroxy-5-ene to 3-oxo-4-ene forms. Shown in the red boxes are 7β,26-diHC and 26H,7O-C, assumed to be interconverted by the HSD11B enzymes. Enzymes, supported by experimental evidence are shown in blue, where activity is assumed enzymes are in green. Diseases resulting from enzymes deficiency are in red and indicated by an X preceding the disease abbreviation.

Figure 2.. Chromatographic separation of mono-hydroxycholesterols, extracted from mouse brain, as Girard P derivatives demonstrating the complexity of the oxysterol profile.

The different oxysterols are labelled with the location of the extra hydroxy group. No authentic standard was available for the oxysterol indicated to be 12α-hydroxycholesterol (12α-HC). As a consequence of derivatisation, each oxysterol may give twin peaks. The top panel shows mono-hydroxycholesterols in the brain from the Cyp27a1 knock-out mouse, the bottom panel is from a wild-type mouse. The Cyp27a1 knock-out mouse biochemically mimics the human disorder CTX, showing an absence of 26-HC and elevation in 7α-HC [30]. In both chromatograms, the y-axis is normalised to the most intense peak at 100% relative abundance (RA). The measured concentration of 24S-HC corresponding to this peak is given in the right-hand corner of each chromatogram. A hydrolysis step was not performed. To generate the reconstructed-ion chromatogram, mass spectrometry data were recorded at high resolution with an Orbitrap analyser. Reproduced from ref. [30].