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 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.

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 The versatility of liver X receptors in T cell homeostasis: Location, location, location!

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Truong San Phan ◽  
Thomas Brunner
Keyword(s):  
T Cell ◽  
Nuclear Receptors ◽  
Target Cells ◽  
Liver X Receptors ◽  
T Cell Homeostasis ◽  
Specific Expression ◽  
Cell Homeostasis ◽  
Cell Type Specific Expression ◽  
X Receptors ◽  
And Function

Nuclear receptors control the transcriptional program of target cells and thereby their phenotype and activities. Two complementary studies by Micheals et al. (https://doi.org/10.1084/jem.20201311) and Chan et al. (https://doi.org/10.1084/jem.20200318) published in JEM uncover the cell type–specific expression and role of the nuclear receptors liver X receptors in the regulation of T cell homeostasis and function.

Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin-bundling protein fascin

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4288-4295 ◽  
Author(s):  
René Geyeregger ◽  
Maximilian Zeyda ◽  
Wolfgang Bauer ◽  
Ernst Kriehuber ◽  
Marcus D. Säemann ◽  
...  
Keyword(s):  
Synapse Formation ◽  
Cholesterol Metabolism ◽  
Interleukin 12 ◽  
Cell Phenotype ◽  
Central Position ◽  
Liver X Receptors ◽  
X Receptors ◽  
And Function ◽  
Immunologic Synapse ◽  
Dc Maturation

Abstract Liver X receptors (LXRs) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data revealed a cross talk between LXR and Toll-like receptor signaling in macrophages, indicating a role in immunity. Here, we show that LXRα is expressed in human myeloid dendritic cells (DCs) and induced during differentiation of monocyte-derived DCs, whereas LXRβ is expressed constitutively at a very low level. LXR activation by 2 different LXR agonists strongly interfered with lipopolysaccharide (LPS)–induced but not with CD40L-induced DC maturation by altering DC morphology and suppressing interleukin-12—but enhancing interleukin-10—secretion. LXR activation in DCs largely blocked their T-cell stimulatory ability despite essentially unaltered expression of various antigen-presenting and costimulatory molecules. Immunologic synapse formation was significantly inhibited by LXR activation along with a complete block in LPS- but not CD40L-induced expression of the actin-bundling protein fascin. Notably, overexpression of fascin in LXR agonist–treated DCs restored immunologic synapse formation and restored their ability to activate T cells. In conclusion, our data reveal LXR as a potent modulator of DC maturation and function mediated in part by blocking the expression of fascin. Due to the central position of DCs in immunity, LXRα could be a potential novel target for immunomodulation.

Transcriptional regulation of macrophage cholesterol trafficking by PPARα and LXR

2006 ◽  
Vol 34 (6) ◽  
pp. 1128-1131 ◽  
Author(s):  
G. Chinetti ◽  
J.C. Fruchart ◽  
B. Staels
Keyword(s):  
Transcription Factors ◽  
Peroxisome Proliferator ◽  
Liver X Receptors ◽  
Cholesterol Trafficking ◽  
Peroxisome Proliferator Activated Receptors ◽  
Atherosclerosis Development ◽  
X Receptors ◽  
And Function ◽  
Atherosclerosis Research

PPARs (peroxisome-proliferator-activated receptors) and LXRs (liver X receptors) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Since the macrophage plays an important role in host defence and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes, including atherosclerosis. Research over the last few years has revealed important roles for PPARs and LXRs in macrophage inflammation and cholesterol homoeostasis with consequences in atherosclerosis development. This review will discuss the role of these transcription factors in the control of cholesterol trafficking in macrophages.

scholarly journals Liver X receptors are required for thymic resilience and T cell output

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Christopher T. Chan ◽  
Ashley M. Fenn ◽  
Nina K. Harder ◽  
John E. Mindur ◽  
Cameron S. McAlpine ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Liver X Receptors ◽  
Cell Repertoire ◽  
Autoimmune Encephalomyelitis ◽  
X Receptors ◽  
And Function ◽  
Mutually Independent

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)—a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity—critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ’s functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ’s indispensable roles in adaptive immunity.

Using integrative lipid systems biology to understand the role of Liver X receptors (LXRs) in male reproduction

2018 ◽  
Author(s):  
Sheba Jarvis ◽  
Lee Gethings ◽  
Raffaella Gadeleta ◽  
Emmanuelle Claude ◽  
Robert Winston ◽  
...  
Keyword(s):  
Systems Biology ◽  
Male Reproduction ◽  
Liver X Receptors ◽  
X Receptors

scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

271 Investigating the Relationship Between Nursery Pig Performance and Markers of Intestinal Morphology and Integrity

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 100-101
Author(s):  
Carson M De Mille ◽  
Nicholas K Gabler
Keyword(s):  
Active Transport ◽  
Feed Intake ◽  
Ex Vivo ◽  
Intestinal Morphology ◽  
Ussing Chambers ◽  
Nursery Pig ◽  
Pig Performance ◽  
Positive Correlations ◽  
And Function ◽  
Time Point

Abstract Weaning induces major structural and function changes to the small intestine of pigs and they transition from milk to solid feedstuffs. Thus, the objective of this study was to determine how intestinal morphology and function markers relate to feed intake and growth rates of nursery pig. Forty-eight weaned pigs (5.63 ± 0.50 kg) were randomly selected, individually penned and fed a common diet. Pig bodyweights and feed intake were determined at d 2, 7, and 21. At each time point, 16 pigs were randomly selected and euthanized. Sections of ileum were assessed for morphology [villus height (VH), crypt depth (CD) and VH:CD] and ex vivo transepithelial resistance (TER), macromolecule permeability (FD4), and active transport of glucose and glutamine via modified Ussing chambers. Within each period (d 0–2, 0–7, and 0–21), Pearson correlations were performed between ADG, ADFI, VH, VH:CD, TER, FD4 and active transport of glucose and glutamine. At d 2 post-weaning, no correlations (P > 0.05) were observed between performance and intestinal variables. By d 7, moderate positive correlations between VH and ADFI (r = 0.69, P = 0.005), VH and ADG (r = 0.68, P = 0.006) were reported. At 21 d post-weaning, moderate positive correlations were still observed for VH and ADFI (r = 0.55, P = 0.026) and between VH and ADG (r = 0.51, P = 0.042). Interestingly, ADFI and ADG tended to be negatively correlated with active glucose transport (r = -0.45, P = 0.083 and r = -0.47, P = 0.064, respectively) and active glutamine transport (r = -0.45, P = 0.083 and r = -0.46, P = 0.073, respectively). Markers of ileal integrity (TER and FD4) were not correlated with ADG or ADFI at any time point. Altogether, these data highlight the importance of intestinal morphology on early nursery pig performance.

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