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Special Issue "Liver X Receptors"

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

Deadline for manuscript submissions: closed (31 October 2019).

Special Issue Editors

Prof. Dr. Jean-Marc A. Lobaccaro
E-Mail Website
Guest Editor
Clermont Université, Université Blaise-Pascal, Clermont, France
Interests: nuclear receptors; prostate; reproduction; lipids; steroids; endocrinology; cancer; ligand screening; mouse models
Special Issues and Collections in MDPI journals
Dr. Silvère Baron
E-Mail Website
Guest Editor
Université Blaise-Pascal, Clermont, France
Interests: nuclear receptors; prostate; reproduction; lipids; steroids; endocrinology; cancer; ligand screening; mouse models
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Almost twenty years ago, David Mangelsdorf’s group identified oxysterols as bona fide ligands for the Liver X Receptors (LXR)α and β, at this time considered as orphan nuclear receptors. Since then, various molecules with the capacity to modulate LXR transcriptional activity have been described.

This Special Issue of IJMS wishes to provide a comprehensive overview of the state-of-the-art of the physiological roles of LXRs from cellular to molecular mechanisms. This Special Issue will also present the putative pathologies associated with a defect in the pathways regulated by the LXRs and the screening of new LXR modulators that could be used in the treatment of these diseases.

Topics include, but are not limited to, the following:

  • Peripheral and/or central nervous system and associated diseases;
  • Hepatic functions of LXRs;
  • Genetic screening of LXR single nucleotide polymorphisms;
  • Interest and development of LXR antagonists;
  • Development and screening of LXR modulators from natural compounds;
  • Use of LXR ligands in the treatment of cancers;
  • Roles of LXRs in lymphocyte physiology;
  • Oxysterols and neurodegenerative diseases;
  • LXRs and atherosclerosis;
  • Modulating LXR activity in colorectal cancer;
  • Mesenchymal cell differentiation and LXRs;
  • LXR and breast cancer;
  • Tumor treatments, immune responses, and LXRs;
  • Physiopathology of LXRs in skin homeostasis;
  • LXRs, oxysterols, and reproduction;
  • Pregnancy, placenta, and LXR regulation;
  • Adipose cell fate and LXR;
  • LXR and cell membrane composition.

You are hence warmly invited to submit original research and review articles related to any of these aspects.


Prof. Dr. Jean-Marc A. Lobaccaro
Dr. Silvère Baron
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 papers will be 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

  • Liver X receptor
  • Oxysterol
  • Cholesterol
  • Lipid metabolism
  • Cancer
  • Dyslipidemia
  • Reproduction
  • Central-peripheral nervous system
  • Immune cells

Published Papers (9 papers)

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Research

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Article
Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells
Int. J. Mol. Sci. 2019, 20(13), 3241; https://doi.org/10.3390/ijms20133241 - 02 Jul 2019
Cited by 9 | Viewed by 2390
Abstract
Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic [...] Read more.
Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review

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Review
Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology
Int. J. Mol. Sci. 2020, 21(4), 1356; https://doi.org/10.3390/ijms21041356 - 17 Feb 2020
Cited by 8 | Viewed by 1700
Abstract
Breast cancer is the most frequent cancer among women. In 2018, it is estimated that 627,000 women died from breast cancer. This is approximately 15% of all cancer deaths among women (WHO 2018). Breast cancer is a multifactorial chronic disease. While important progress [...] Read more.
Breast cancer is the most frequent cancer among women. In 2018, it is estimated that 627,000 women died from breast cancer. This is approximately 15% of all cancer deaths among women (WHO 2018). Breast cancer is a multifactorial chronic disease. While important progress has been made to treat patients, many questions regarding aspects of this disease relating to carcinogenesis are still open. During carcinogenesis, cells exhibit cholesterol homeostasis deregulation. This results in an accumulation of intracellular cholesterol, which is required to sustain their high growth rate. Cholesterol efflux and influx are two metabolic pathways that are necessary to prevent cholesterol accumulation in the cells. Liver X receptors (LXRs) are nuclear receptors that, upon activation, induce the expression of ABC transporters, responsible for promoting cholesterol efflux, and the expression of IDOL (inducible degrader of low-density lipoprotein receptor), in charge of reducing cholesterol influx. Oxysterols, oxygenated derivatives of cholesterol formed through different pathways, have been discovered as LXR-specific ligands. Some oxysterols are involved in tumor formation while others are considered anti-tumor agents. In the present review, we discuss the involvement of cholesterol, oxysterols and LXRs in breast cancer pathophysiology, with an emphasis on the biological effects of LXR ligands. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Liver X Receptors and Male (In)fertility
Int. J. Mol. Sci. 2019, 20(21), 5379; https://doi.org/10.3390/ijms20215379 - 29 Oct 2019
Cited by 5 | Viewed by 1391
Abstract
Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. [...] Read more.
Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells
Int. J. Mol. Sci. 2019, 20(20), 5045; https://doi.org/10.3390/ijms20205045 - 11 Oct 2019
Cited by 17 | Viewed by 2250
Abstract
Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate [...] Read more.
Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate cells, which leads to persistent inflammation and fibrosis. The nuclear receptors liver X receptor α (LXRα) and LXRβ act as negative regulators of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway. Additionally, LXRs exert an anti-inflammatory effect in immune cell types, such as macrophages. LXR activation suppresses acute hepatic inflammation that is mediated by Kupffer cells/macrophages. Acute liver injury, diet-induced steatohepatitis, and fibrosis are exacerbated by significant hepatic cholesterol accumulation and inflammation in LXR-deficient mice. Therefore, LXRs regulate hepatic lipid metabolism and immunity and they are potential therapeutic targets in the treatment of hepatic inflammation that is associated with cholesterol accumulation. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Oxysterols in Autoimmunity
Int. J. Mol. Sci. 2019, 20(18), 4522; https://doi.org/10.3390/ijms20184522 - 12 Sep 2019
Cited by 18 | Viewed by 1758
Abstract
Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. Studies from the last few decades have demonstrated [...] Read more.
Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. Studies from the last few decades have demonstrated that oxysterols are not only active metabolites but are further involved in the modulation of immune responses. Liver X Receptors (LXRs), nuclear receptors for oxysterols, are important for cholesterol homeostasis and regulation of inflammatory response but are still poorly characterized during autoimmune diseases. Here we review the current knowledge about the role of oxysterols during autoimmune conditions and focus on the implication of LXR-dependent and LXR-independent pathways. We further highlight the importance of these pathways in particular during central nervous system (CNS) autoimmunity and inflammatory bowel diseases (IBD) in both experimental models and human studies. Finally, we discuss our vision about future applications and research on oxysterols related to autoimmunity. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Xenobiotic Receptors and Their Mates in Atopic Dermatitis
Int. J. Mol. Sci. 2019, 20(17), 4234; https://doi.org/10.3390/ijms20174234 - 29 Aug 2019
Cited by 7 | Viewed by 1590
Abstract
Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis [...] Read more.
Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called ‘atopic march’. Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Liver X Receptors and Their Implications in the Physiology and Pathology of the Peripheral Nervous System
Int. J. Mol. Sci. 2019, 20(17), 4192; https://doi.org/10.3390/ijms20174192 - 27 Aug 2019
Cited by 2 | Viewed by 1811
Abstract
Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in [...] Read more.
Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?
Int. J. Mol. Sci. 2019, 20(16), 3858; https://doi.org/10.3390/ijms20163858 - 08 Aug 2019
Cited by 19 | Viewed by 1959
Abstract
Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among [...] Read more.
Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients. Full article
(This article belongs to the Special Issue Liver X Receptors)
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Review
Revisiting the Role of LXRs in PUFA Metabolism and Phospholipid Homeostasis
Int. J. Mol. Sci. 2019, 20(15), 3787; https://doi.org/10.3390/ijms20153787 - 02 Aug 2019
Cited by 8 | Viewed by 1564
Abstract
Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, [...] Read more.
Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases. Full article
(This article belongs to the Special Issue Liver X Receptors)
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