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Impact of Cholesterol and Sterol Derivatives on Pathogenetic Mechanisms and on the Therapy of Neuropsychiatric Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 4257

Special Issue Editor


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Guest Editor
1. Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain
2. Network Center for Neurodegenerative Disease Research (CiberNed), Instituto de Salud Carlos III, Madrid, Spain
Interests: Alzheimer; pharmacology; neuroscience; membrane receptors and intercellular communication
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As cholesterol is key for neural cell function, scientists are slowly incorporating the idea that hypercholesterolemia is a foe that negatively impacts on the plastic changes that lead to neurodegenerative diseases and that affect the appearance of psychotic episodes in neuropsychiatric patients. On the one hand, this vision should be reviewed since cholesterol cannot cross the blood–brain barrier, that is, cholesterol is synthesized in situ by the cells of the central nervous system. On the other hand, sterols, both endogenous and present in food and beverages, affect neuronal function. Finally, there are controversies about the advisability of using hypocholesterolemic agents that enter the brain, that is, what is more appropriate: using drugs that enter the brain or those that inhibit the formation of cholesterol only in the periphery. In summary, this Special Topic is open to original reports or reviews covering any aspect related to the relationship between neuropsychiatric diseases and cholesterol and sterols in brain. The overall objective is to improve our knowledge about pathogenic mechanisms and explore new therapy opportunities.

Dr. Rafael Franco
Guest Editor

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Keywords

  • cholesterol
  • sitosterol
  • Alzheimer’s disease
  • autism spectrum disorders
  • schizophrenia
  • vascular dementia

Published Papers (1 paper)

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Research

13 pages, 1948 KiB  
Article
Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation
by Hiroshi Matsuoka, Miyu Katayama, Ami Ohishi, Kaoruko Miya, Riki Tokunaga, Sou Kobayashi, Yuya Nishimoto, Kazutake Hirooka, Akiho Shima and Akihiro Michihara
Int. J. Mol. Sci. 2020, 21(9), 3309; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093309 - 07 May 2020
Cited by 9 | Viewed by 3847
Abstract
Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the [...] Read more.
Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the major pathway for oxysterol elimination, followed by oxidation through hepatic first-pass metabolism by CYP39A1. Abnormal CYP39A1 expression results in accumulation of 24S-OHC, influencing neurodegenerative disease-related deterioration; thus, it is important to understand the normal elimination of 24S-OHC and the system regulating CYP39A1, a selective hepatic metabolic enzyme of 24S-OHC. We examined the role of transcriptional regulation by retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses. Full article
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