Abstract
The two oxysterols, 27-hydroxycholesterol (27OH) and 24S-hydroxycholesterol (24OH), are both inhibitors of cholesterol synthesis and activators of the liver X receptor (LXR) in vitro. Their role as physiological regulators under in vivo conditions is controversial, however. In the present work, we utilized a previously described mouse model with overexpressed human sterol 27-hydroxylase (CYP27A1). The levels of 27OH were increased about 12-fold in the brain. The brain levels of HMG-CoA reductase mRNA and HMG-CoA synthase mRNA levels were increased. In accordance with increased cholesterol synthesis, most of the cholesterol precursors were also increased. The level of 24OH, the dominating oxysterol in the brain, was decreased by about 25%, most probably due to increased metabolism by CYP27A1. The LXR target genes were unaffected or slightly changed in a direction opposite to that expected for LXR activation. In the brain of Cyp27(-/-) mice, cholesterol synthesis was slightly increased, with increased levels of cholesterol precursors but normal mRNA levels of HMG-CoA reductase and HMG-CoA synthase. The mRNA levels corresponding to LXR target genes were not affected. The results are consistent with the possibility that both 24OH and 27OH are physiological suppressors of cholesterol synthesis in the brain. The results do not support the contention that 27OH is a general activator of LXR target genes in this organ.
Highlights
The two oxysterols, 27-hydroxycholesterol (27OH) and 24S-hydroxycholesterol (24OH), are both inhibitors of cholesterol synthesis and activators of the liver X receptor (LXR) in vitro
We have studied the effect of an overexpression of the sterol 27-hydroxylase (CYP27A1) enzyme on cholesterol synthesis and LXR-targeted genes in the brain of mice
We showed that a knockout of the Cyp27a1 gene causes a slight upregulation of cholesterol synthesis in mouse brain [12]
Summary
The two oxysterols, 27-hydroxycholesterol (27OH) and 24S-hydroxycholesterol (24OH), are both inhibitors of cholesterol synthesis and activators of the liver X receptor (LXR) in vitro. Causes a suppressed synthesis, reduced absorption from the intestine, and increased rate of degradation into bile acids The latter two effects are mediated by the nuclear liver X receptor (LXR) [2]. There are three different mechanisms by which the oxysterols may affect cholesterol-sensitive genes: 1) interaction with the sterol-regulatory element binding proteins (SREBP mechanism); 2) activation of the LXR mechanisms; and 3) effects on the degradation of specific enzymes, in particular HMG-CoA reductase (HMGCR). There is a constant flux of 24OH from the brain across the blood-brain barrier into the circulation This oxysterol is taken up by the liver and converted into bile acids and conjugates of unmetabolized or partially metabolized 24OH [4].
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