Importance of a Novel Oxidative Mechanism for Elimination of Brain Cholesterol

Björkhem, Ingemar; Lütjohann, Dieter; Breuer, Olof; Sakinis, Augustinas; Wennmalm, Åke

doi:10.1074/jbc.272.48.30178

Cited by 251 publications

(98 citation statements)

References 26 publications

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“…This fi nding indicates that the spinal cord may have a relatively high capacity for excretion of cholesterol. In the brain, the most important mechansm for this excretion is conversion of cholesterol into 24S-hydroxycholesterol, which is able to pass the blood-brain barrier ( 21,22 ). The levels of the enzyme cholesterol 24S-hydroxylase are very low in the spinal cord in relation to the corresponding levels in the brain, indicating that there must be another mechanism for removal of the excess cholesterol from the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Schüle

Siddique

Deng

et al. 2010

Journal of Lipid Research

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102

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Section: Discussionmentioning

confidence: 99%

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Schüle

Siddique

Deng

et al. 2010

Journal of Lipid Research

Self Cite

102

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“…A continuous turnover of cholesterol in neurons facilitates cell ability for efficient and quick adaptation of cholesterol homeostasis required for dynamic structural changes of neurons, their extensions, and their synapses during synaptic plasticity (43). Conversion of cholesterol into 24(S)-hydroxycholesterol, which is also a brain-specific LXR ligand, by CYP46 represents a major route for cholesterol turnover in neurons (44).…”

Section: Discussionmentioning

confidence: 99%

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Abildayeva

Jansen

Hirsch‐Reinshagen

et al. 2006

Journal of Biological Chemistry

218

188

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Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has beenhypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose-and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10 -20-fold higher basal LXR␣ and -␤ expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.

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“…The majority of circulating 24-hydroxycholesterol in the mouse (8), rat (16), and human (17) is made in the brain. The brain is the most cholesterol-rich tissue in mammals and, unlike peripheral tissues, cannot exchange cholesterol with circulating lipoprotein particles (11).…”

Section: Discussionmentioning

confidence: 99%

Expression Cloning of an Oxysterol 7α-Hydroxylase Selective for 24-Hydroxycholesterol

Li-Hawkins

Lund

Bronson

et al. 2000

Journal of Biological Chemistry

172

131

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The synthesis of 7␣-hydroxylated bile acids from oxysterols requires an oxysterol 7␣-hydroxylase encoded by the Cyp7b1 locus. As expected, mice deficient in this enzyme have elevated plasma and tissue levels of 25-and 27-hydroxycholesterol; however, levels of another major oxysterol, 24-hydroxycholesterol, are not increased in these mice, suggesting the presence of another oxysterol 7␣-hydroxylase. Here, we describe the cloning and characterization of murine and human cDNAs and genes that encode a second oxysterol 7␣-hydroxylase. The genes contain 12 exons and are located on chromosome 6 in the human (CYP39A1 locus) and in a syntenic position on chromosome 17 in the mouse (Cyp39a1 locus). CYP39A1 is a microsomal cytochrome P450 enzyme that has preference for 24-hydroxycholesterol and is expressed in the liver. The levels of hepatic CYP39A1 mRNA do not change in response to dietary cholesterol, bile acids, or a bile acid-binding resin, unlike those encoding other sterol 7␣-hydroxylases. Hepatic CYP39A1 expression is sexually dimorphic (female > male), which is opposite that of CYP7B1 (male > female). We conclude that oxysterol 7␣-hydroxylases with different substrate specificities exist in mice and humans and that sexually dimorphic expression patterns of these enzymes in the mouse may underlie differences in bile acid metabolism between the sexes.Two metabolic pathways that differ in their initial steps produce 7␣-hydroxylated bile acids (1). In one pathway, cholesterol (5-cholesten-3␤-ol) is first converted into 7␣-hydroxycholesterol (cholest-5-ene-3␤,7␣-diol) by the enzyme cholesterol 7␣-hydroxylase, which is encoded by the Cyp7a1 gene in mice. In the other pathway, cholesterol is first converted into one of several oxysterols prior to being 7␣-hydroxylated by oxysterol 7␣-hydroxylase, which is encoded by the Cyp7b1 gene. The 7␣-hydroxylated intermediates produced by these different initiating steps are subsequently converted into primary bile acids by a series of shared enzymes in the liver (2).Cholesterol 7␣-hydroxylase shows a marked preference for cholesterol as a substrate and is only weakly active against other sterols (3), whereas oxysterol 7␣-hydroxylase prefers 25-hydroxycholesterol (cholest-5-ene-3␤,25-diol) and 27-hydroxycholesterol (cholest-5-ene-3␤,27-diol) (4, 5). In agreement with the latter preference, Cyp7b1 knockout mice accumulate these two oxysterols in their plasma and tissues (6). The levels of the other major oxysterol, 24-hydroxycholesterol (cholest-5-ene-3␤,24-diol), are near normal in these animals (6). In contrast, a human with a complete absence of oxysterol 7␣-hydroxylase activity accumulated 24-hydroxycholesterol as well as 25-and 27-hydroxycholesterol in his plasma (7). These observations suggest that the human enzyme, unlike the mouse enzyme, may act on all three oxysterol substrates.The observed differences in the oxysterol accumulation patterns in mice and humans that express no oxysterol 7␣-hydroxylase are not due to differences in the biosynthesis of oxysterols, as cholester...

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Importance of a Novel Oxidative Mechanism for Elimination of Brain Cholesterol

Cited by 251 publications

References 26 publications

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Expression Cloning of an Oxysterol 7α-Hydroxylase Selective for 24-Hydroxycholesterol

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