Liver X receptor: from metabolism to cancer

2014 ◽  
Vol 459 (2) ◽  
pp. e1-e3 ◽  
Author(s):  
Nicolas Venteclef ◽  
Pascal Ferré
Keyword(s):  
Mammalian Cells ◽  
Interferon Γ ◽  
Liver X Receptors ◽  
Biochemical Journal ◽  
Important Regulator ◽  
Ifn Γ ◽  
New Perspective ◽  
X Receptors ◽  
And Function ◽  
Lxr Agonists

Cholesterol plays an indispensable role in regulating the properties of cell membranes in mammalian cells. Accumulation of cholesterol and its intermediates, such as oxysterols, lead to activation of the nuclear receptors LXRs (liver X receptors). LXR is an important regulator of cholesterol homoeostasis by controlling its transport and its neo-synthesis. Accumulating evidence indicates that the endogenous ligands of LXRs, oxysterols, play an active and important role in regulating the fate and function of immune cells. Indeed, LXRs are negative regu-lators of innate immunity by interfering with macrophage activation. Recent advances have highlighted a controversial role for LXR in cancer. In this issue of the Biochemical Journal, Wang et al. propose that LXR agonist directly controls IFN-γ (interferon-γ) expression, which limits tumour growth. This protective effect mediated by LXR appears to be dependent on IFN-γ. Thus, despite accumulation of endogenous ligand of LXR in cancer, activation of LXR seems protective. This novel evidence provides a new perspective for targeting LXR in cancer, although controversial studies can be also found in the literature. In order to avoid side effects associated with LXR agonists, molecular and cellular studies are required to decipher this unexpected action of LXRs.

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

scholarly journals The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation

2016 ◽  
Vol 213 (4) ◽  
pp. 585-603 ◽  
Author(s):  
David Langlais ◽  
Luis B. Barreiro ◽  
Philippe Gros
Keyword(s):  
Pulmonary Tuberculosis ◽  
Mouse Models ◽  
Chromatin Immunoprecipitation ◽  
Inflammatory Diseases ◽  
Transcriptional Regulators ◽  
Interferon Γ ◽  
Wild Type ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Ifn Γ ◽  
And Function

IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by proinflammatory signals such as interferon-γ (IFN-γ). Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all of the genes bound by (cistromes) and transcriptionally activated by (regulomes) IRF8, IRF1, PU.1, and STAT1, including modulation of epigenetic histone marks. Of the seven binding combinations identified, two (cluster 1 [IRF8/IRF1/STAT1/PU.1] and cluster 5 [IRF1/STAT1/PU.1]) were found to have a major role in controlling macrophage transcriptional programs both at the basal level and after IFN-γ activation. They direct the expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and antimicrobial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immunodeficiencies and with loci associated with several inflammatory diseases in humans.

scholarly journals The Secretome of Liver X Receptor Agonist Treated Early Outgrowth Cells Decreases Atherosclerosis in Ldlr-/- Mice

2019 ◽  
Author(s):  
Adil Rasheed ◽  
Sarah Shawky ◽  
Ricky Tsai ◽  
Richard G Jung ◽  
Trevor Simard ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Plaque Burden ◽  
Liver X Receptors ◽  
Aortic Sinus ◽  
Secreted Factors ◽  
Early Outgrowth Cells ◽  
Lineage Markers ◽  
X Receptors ◽  
And Function ◽  
Early Atherosclerosis

AbstractObjectiveEndothelial progenitor cells (EPCs) promote the maintenance of the endothelium by the secretion of vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) are currently being investigated as novel cell-based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver x receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR gain-of-function in EOCs is beneficial for the treatment of atherosclerosis.Approach and ResultsEOCs were differentiated from the bone marrow of wildtype (WT) and LXR-knockout (Lxrαβ-/-) mice in the presence of vehicle or LXR agonist (GW3965). WT EOCs treated with GW3965 throughout differentiation showed reduced expression of endothelial lineage markers (Cd144, Vegfr2) compared to WT vehicle and Lxrαβ-/- cells. GW3965-treated EOCs produced secreted factors that reduced monocyte adhesion to activated endothelial cells in culture. When injected into atherosclerosis-prone Ldlr-/- mice, GW3965-treated EOCs and concentrated conditioned media (CM) from GW3965-treated EOCs, reduced plaque burden within the aortic sinus. Furthermore, when CM from human EOCs (obtained from patients with established CAD) were treated with GW3965, monocyte to endothelial adhesion was decreased suggesting the translatability of the results.ConclusionsEx vivo LXR agonist treatment of EOCs produces a secretome that decreases early atherosclerosis in Ldlr-/- mice. CM from human EOCs significantly inhibits monocyte to endothelial adhesion. Thus, active factor(s) within the GW3965-treated EOC secretome have the potential to be useful for the treatment of atherosclerosis.

scholarly journals Liver X Receptors (LXRs) Regulate Apolipoprotein AIV-Implications of the Antiatherosclerotic Effect of LXR Agonists

2004 ◽  
Vol 18 (8) ◽  
pp. 2000-2010 ◽  
Author(s):  
Yu Liang ◽  
Xian-Cheng Jiang ◽  
Ruijie Liu ◽  
Guosheng Liang ◽  
Thomas P. Beyer ◽  
...  
Keyword(s):  
Liver X Receptors ◽  
Antiatherosclerotic Effect ◽  
X Receptors ◽  
Lxr Agonists

scholarly journals Liver X Receptors as potential therapeutic targets in atherosclerosis

2009 ◽  
Vol 32 (5) ◽  
pp. 383 ◽  
Author(s):  
Yanfei Zhu ◽  
Yousheng Li
Keyword(s):  
Cardiovascular Disease ◽  
First Generation ◽  
Cholesterol Transport ◽  
Therapeutic Effects ◽  
Liver X Receptors ◽  
Hepatic Lipogenesis ◽  
Current State ◽  
Selective Agonists ◽  
X Receptors ◽  
Lxr Agonists

Purpose: Atherosclerosis is the primary independent risk factor of cardiovascular disease, and Liver X Receptors (LXR? and LXR?) activation may play an anti-atherosclerosis effect. In this article, we summarize the current state of knowledge of roles of LXRs in physiology and homeostasis as well as the links between LXR action and atherosclerosis, and discuss the potential therapeutic effects of LXR agonists. Source: A MEDLINE database search was performed to identify relevant articles using the keywords “liver X receptors”, “LXRs”, and “atherosclerosis”. Additional papers were identified by a manual research of the references from the key articles. Principle findings: Both LXR isoforms promote reverse cholesterol transport (RCT) and have anti-inflammatory activity. LXR? is the predominant receptor in the liver regulating triglyceride synthesis. The antiatherosclerotic ability of LXRs makes them attractive targets for drugs for the treatment of cardiovascular disease. However, LXR activation induces lipogenesis and hypertriglyceridemia. The first-generation synthetic ligands of LXR increase hepatic lipogenesis and plasma triglyceride levels. New LXR ligands need to be designed without undesirable side effects. Conclusion: LXR ?-selective agonists and LXR modulators, which act as agonists in macrophages and induce cholesterol efflux while as antagonists of lipogenesis in the liver, are two critical and attractive approaches to treat atherosclerosis and cardiovascular diseases.

scholarly journals Development of Agonist-Based PROTACs Targeting Liver X Receptor

2021 ◽  
Vol 9 ◽  
Author(s):  
Hanqiao Xu ◽  
Nobumichi Ohoka ◽  
Hidetomo Yokoo ◽  
Kanako Nemoto ◽  
Takashi Ohtsuki ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Nuclear Hormone Receptor ◽  
Cholesterol Homeostasis ◽  
Lipid Homeostasis ◽  
Liver X Receptors ◽  
Ubiquitin Proteasome ◽  
Antagonists And Inhibitors ◽  
X Receptors ◽  
And Function ◽  
Complementary Strategy

Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily and function as ligand-dependent transcription factors that regulate cholesterol homeostasis, lipid homeostasis, and immune responses. LXR antagonists are promising treatments for hypercholesterolemia and diabetes. However, effective LXR antagonists and inhibitors are yet to be developed. Thus, we aimed to develop LXR degraders (proteolysis targeting chimeras PROTACs against LXR) as a complementary strategy to provide a similar effect to LXR inhibition. In this study, we report the development of GW3965-PEG5-VH032 (3), a PROTAC capable of effectively degrading LXRβ protein. Compound 3 induced the ubiquitin-proteasome system-dependent degradation of the LXRβ protein, which requires VHL E3 ligase. We hope that PROTACs targeting LXR proteins will become novel therapeutic agents for LXR-related diseases.

scholarly journals Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

2013 ◽  
Vol 190 (12) ◽  
pp. 6520-6532 ◽  
Author(s):  
Mónica Pascual-García ◽  
Laura Rué ◽  
Theresa León ◽  
Josep Julve ◽  
José María Carbó ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cross Talk ◽  
Inflammatory Responses ◽  
Liver X Receptors ◽  
Ifn Γ ◽  
X Receptors

scholarly journals Involvement of Tweak in Interferon γ–Stimulated Monocyte Cytotoxicity

2000 ◽  
Vol 192 (9) ◽  
pp. 1373-1380 ◽  
Author(s):  
Masafumi Nakayama ◽  
Nobuhiko Kayagaki ◽  
Noriko Yamaguchi ◽  
Ko Okumura ◽  
Hideo Yagita
Keyword(s):  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Squamous Carcinoma ◽  
Interferon Γ ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ ◽  
Squamous Carcinoma Cell ◽  
And Function ◽  
Monocyte Cytotoxicity ◽  
Necrosis Factor

TWEAK, a new member of the tumor necrosis factor (TNF) family, induces cell death in some tumor cell lines, but its physiological functions are largely unknown. In this study, we investigated the expression and function of TWEAK in human peripheral blood mononuclear cells (PBMCs) by using newly generated anti–human TWEAK mAbs. Although freshly isolated PBMCs expressed no detectable level of TWEAK on their surfaces, a remarkable TWEAK expression was rapidly observed on monocytes upon stimulation with interferon (IFN)-γ but not with IFN-α or lipopolysaccharide. Cytotoxic activity of IFN-γ–stimulated monocytes against human squamous carcinoma cell line HSC3 was inhibited partially by anti-TWEAK mAb alone and almost completely by combination with anti-TRAIL (TNF-related apoptosis-inducing ligand) mAb. These results revealed a novel pathway of monocyte cytotoxicity against tumor cells that is mediated by TWEAK and potentiated by IFN-γ.

scholarly journals Interferon γ Signaling Alters the Function of T Helper Type 1 Cells

2000 ◽  
Vol 192 (7) ◽  
pp. 977-986 ◽  
Author(s):  
Gregory Z. Tau ◽  
Thierry von der Weid ◽  
Binfeng Lu ◽  
Simone Cowan ◽  
Marina Kvatyuk ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Ifn Γ ◽  
And Function

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon γ receptor (IFN-γR), whereas Th1 cells do not express the second chain of the IFN-γR (IFN-γR2) and are therefore unresponsive to IFN-γ. To determine whether the regulation of IFN-γR2 expression, and therefore IFN-γ responsiveness, is important for the differentiation of naive CD4+ T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-γR2 is controlled by the CD2 promoter and enhancer. CD4+ T cells from IFN-γR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-γ production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-γR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-γ–unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.

scholarly journals IFN-γ downregulates expression of Na+/H+exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells

2001 ◽  
Vol 280 (5) ◽  
pp. C1224-C1232 ◽  
Author(s):  
Flavio Rocha ◽  
Mark W. Musch ◽  
Leonid Lishanskiy ◽  
Cres Bookstein ◽  
Kazunori Sugi ◽  
...  
Keyword(s):  
Protein Expression ◽  
Membrane Vesicles ◽  
Interferon Γ ◽  
Northern Blotting ◽  
Intestinal Epithelial ◽  
Rat Intestine ◽  
Adult Rats ◽  
Bowel Diseases ◽  
Ifn Γ ◽  
And Function

Diarrhea associated with inflammatory bowel diseases has traditionally been attributed to stimulated secretion. The purpose of this study was to determine whether chronic stimulation of intestinal mucosa by interferon-γ (IFN-γ) affects expression and function of the apical membrane Na+/H+exchangers NHE2 and NHE3 in rat intestine and Caco-2/bbe (C2) cells. Confluent C2 cells expressing NHE2 and NHE3 were treated with IFN-γ for 2, 24, and 48 h. Adult rats were injected with IFN-γ intraperitoneally for 12 and 48 h. NHE2 and NHE3 activities were measured by unidirectional22Na influx across C2 cells and in rat brush-border membrane vesicles. NHE protein and mRNA were assessed by Western and Northern blotting. IFN-γ treatment of C2 monolayers caused a >50% reduction in NHE2 and NHE3 activities and protein expression. In rats, region-specific, time- and dose-dependent reductions of NHE2 and NHE3 activities, protein expression, and mRNA were observed after exposure to IFN-γ. Chronic exposure of intestinal epithelial cells to IFN-γ results in selective downregulation of NHE2 and NHE3 expression and activity, a potential cause of inflammation-associated diarrhea.

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