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Disorders of Cholesterol Homeostasis
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Disorders of Cholesterol Homeostasis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 7586

Special Issue Editors

Dr. Kevin R. Francis

E-Mail Website
Guest Editor
Sanford Research, Cellular Therapies and Stem Cell Biology Group, Sioux Falls, SD, USA
Interests: Cholesterol; Lipids; Trafficing; Cholesterol Synthesis
Dr. Christopher A. Wassif

E-Mail Website
Guest Editor
National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA
Interests: genetics; lysosomal storage diseases; cholesterol metabolism; smith-lemli-opitz syndrome; niemann-tick type C; battens

Special Issue Information

Dear Colleagues,

Cholesterol plays a key role in numerous cellular process and perturbations in synthesis, uptake, trafficking, and metabolism, resulting in a myriad of behavioral, developmental, endocrine, and neurodegenerative defects. Multiple genetic disorders have been identified, each caused by mutations in different enzymatic steps within the cholesterol synthesis pathway, while others have been identified in the trafficking of cholesterol such as NPC and Tangier disease. The associated disorders are often thought of as discrete disorders, with their own clinical signature and yet studies have begun to unravel hints of underlying mechanisms, such as reduced levels of cholesterol in multiple disorders resulting in changes to the morphogen and sonic in early developmental stages leading to the convergences of some clinical features.

Dr. Kevin R. Francis
Dr. Christopher A. Wassif
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cholesterol
  • lipids
  • trafficking
  • cholesterol synthesis
  • metabolism

Published Papers (2 papers)

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Research

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23 pages, 2919 KiB  
Article
Targeted Suppression of Lipoprotein Receptor LSR in Astrocytes Leads to Olfactory and Memory Deficits in Mice
by Aseel El Hajj, Ameziane Herzine, Gaetano Calcagno, Frédéric Désor, Fathia Djelti, Vincent Bombail, Isabelle Denis, Thierry Oster, Catherine Malaplate, Maxime Vigier, Sandra Kaminski, Lynn Pauron, Catherine Corbier, Frances T. Yen, Marie-Claire Lanhers and Thomas Claudepierre
Int. J. Mol. Sci. 2022, 23(4), 2049; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042049 - 12 Feb 2022
Cited by 2 | Viewed by 2071
Abstract
Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia–neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays [...] Read more.
Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia–neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays an important role in brain cholesterol homeostasis. Aged heterozygote Lsr+/− mice show altered brain cholesterol distribution and increased susceptibility to amyloid stress. Since LSR expression is higher in astroglia as compared to neurons, we sought to determine if astroglial LSR deficiency could lead to cognitive defects similar to those of Alzheimer’s disease (AD). Cre recombinase was activated in adult Glast-CreERT/lsrfl/fl mice by tamoxifen to induce astroglial Lsr deletion. Behavioral phenotyping of young and old astroglial Lsr KO animals revealed hyperactivity during the nocturnal period, deficits in olfactory function affecting social memory and causing possible apathy, as well as visual memory and short-term working memory problems, and deficits similar to those reported in neurodegenerative diseases, such as AD. Furthermore, GFAP staining revealed astroglial activation in the olfactory bulb. Therefore, astroglial LSR is important for working, spatial, and social memory related to sensory input, and represents a novel pathway for the study of brain aging and neurodegeneration. Full article
(This article belongs to the Special Issue Disorders of Cholesterol Homeostasis)
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Review

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24 pages, 5643 KiB  
Review
Development of Novel siRNA Therapeutics: A Review with a Focus on Inclisiran for the Treatment of Hypercholesterolemia
by Oluwakemi Ebenezer, Pietro Comoglio, Gane Ka-Shu Wong and Jack A. Tuszynski
Int. J. Mol. Sci. 2023, 24(4), 4019; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044019 - 16 Feb 2023
Cited by 9 | Viewed by 4883
Abstract
Over the past two decades, it was discovered that introducing synthetic small interfering RNAs (siRNAs) into the cytoplasm facilitates effective gene-targeted silencing. This compromises gene expression and regulation by repressing transcription or stimulating sequence-specific RNA degradation. Substantial investments in developing RNA therapeutics for [...] Read more.
Over the past two decades, it was discovered that introducing synthetic small interfering RNAs (siRNAs) into the cytoplasm facilitates effective gene-targeted silencing. This compromises gene expression and regulation by repressing transcription or stimulating sequence-specific RNA degradation. Substantial investments in developing RNA therapeutics for disease prevention and treatment have been made. We discuss the application to proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to and degrades the low-density lipoprotein cholesterol (LDL-C) receptor, interrupting the process of LDL-C uptake into hepatocytes. PCSK9 loss-of-function modifications show significant clinical importance by causing dominant hypocholesterolemia and lessening the risk of cardiovascular disease (CVD). Monoclonal antibodies and small interfering RNA (siRNA) drugs targeting PCSK9 are a significant new option for managing lipid disorders and improving CVD outcomes. In general, monoclonal antibodies are restricted to binding with cell surface receptors or circulating proteins. Similarly, overcoming the intracellular and extracellular defenses that prevent exogenous RNA from entering cells must be achieved for the clinical application of siRNAs. N-acetylgalactosamine (GalNAc) conjugates are a simple solution to the siRNA delivery problem that is especially suitable for treating a broad spectrum of diseases involving liver-expressed genes. Inclisiran is a GalNAc-conjugated siRNA molecule that inhibits the translation of PCSK9. The administration is only required every 3 to 6 months, which is a significant improvement over monoclonal antibodies for PCSK9. This review provides an overview of siRNA therapeutics with a focus on detailed profiles of inclisiran, mainly its delivery strategies. We discuss the mechanisms of action, its status in clinical trials, and its prospects. Full article
(This article belongs to the Special Issue Disorders of Cholesterol Homeostasis)
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