Cholesterol 24S-hydroxylase: Involvement in Brain Injury and Disease.
Cartagena, Casandra Marie
Here we investigated whether traumatic brain injury (TBI) altered the regulation of cholesterol 24S-hydroxylase (Cyp46), an enzyme that converts cholesterol to the more hydrophilic 24S-hydroxycholesterol. We examined changes in Cyp46 expression in rats following fluid percussion injury. Under normal conditions, most Cyp46 was present in neurons, with very little measurable in glia. However, Cyp46 levels were significantly increased in microglia after TBI. 24-hydroxycholesterol induces activation of genes through the liver X receptor (LXR), and here we show apolipoprotein E (ApoE) and ATP-binding cassette transporter (ABC) A1 were increased after TBI, indicating that increased LXR activity coincided with increased Cyp46 levels. We found that activation of primary rat microglia by LPS in vitro caused increased Cyp46 levels. These data suggest that increased microglial Cyp46 activity is part of a system for removal of damaged cell membranes post-injury, by conversion of cholesterol to 24-hydroxycholesterol and by activation of LXR-regulated gene transcription. We also took a systematic look at the effects of 24S-hydroxycholesterol on fatty acid and cholesterol synthesis enzymes, initially focusing on the lipid regulatory proteins SREBP-1 and -2. In three different cell lines, 24S-hydroxycholesterol decreased SREBP-2 and increased levels of LXR regulated SREBP-1. In SY5Y neuroblastomas cells, 24S-hydroxycholesterol decreased cholesterol synthesis enzyme mRNA levels but did not alter fatty synthesis enzyme mRNA levels. In contrast, BV2 microglia 24S-hydroxycholesterol significantly increased mRNA levels of fatty acid synthesis enzymes but had no significant effect on cholesterol synthesis enzymes. After TBI we found that, consistent with the in vitro results, SREBP-1 mRNA levels were increased while SREBP-2 mRNA levels were decreased. Cholesterol synthesis enzymes were significantly decreased after TBI, which we attribute to 24S-hydroxycholesterol activity. However, mRNA levels of the rate limiting step in fatty acid synthesis, acetyl CoA carboxylase were also significantly decreased which could not be due to the effects of 24S-hydroxycholesterol. Thus, other negative feed back mechanisms regulating fatty acid synthesis must be activated after TBI.
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