ArticleMolecular neurobiology2015
Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells.
Article in Molecular neurobiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Punica granatum L. peel extract mitigates hyperlipidemia-induced cognitive impairments in zebrafish larvae via modulating LXR signaling.Metabolic brain disease · 2026Article
- CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Astrocyte-neuron combined targeting for CYP46A1 gene therapy in Huntington's disease.Acta neuropathologica communications · 2025Article
- The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.Current issues in molecular biology · 2025Review
- Effects of Complete and Partial Loss of the 24S-Hydroxycholesterol-Generating EnzymeBiomolecules · 2024Article
- Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis.Cell reports. Medicine · 2023Article
- Defects of Nutrient Signaling and Autophagy in Neurodegeneration.Frontiers in cell and developmental biology · 2022Review
- Altered Cholesterol Homeostasis in Huntington's Disease.Frontiers in aging neuroscience · 2022Review
- Targeting cytochrome P450 46A1 and brain cholesterol 24-hydroxylation to treat neurodegenerative diseases.Exploration of neuroprotective therapy · 2021Article
- LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1.Scientific reports · 2019Article
- The key genes, phosphoproteins, processes, and pathways affected by efavirenz-activated CYP46A1 in the amyloid-decreasing paradigm of efavirenz treatment.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Article
- Article
- Neuronal cholesterol metabolism increases dendritic outgrowth and synaptic markers via a concerted action of GGTase-I and Trk.Scientific reports · 2016Article
- LXR Regulation of Brain Cholesterol: From Development to Disease.Trends in endocrinology and metabolism: TEM · 2016Review
- Role of Liver X Receptor in AD Pathophysiology.PloS one · 2015Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.
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