scholarly journals Inflammation Triggers Liver X Receptor-Dependent Lipogenesis

2019 ◽  
Vol 40 (2) ◽  
Author(s):  
Sophie R. Liebergall ◽  
Jerry Angdisen ◽  
Shun Hang Chan ◽  
YingJu Chang ◽  
Timothy F. Osborne ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Acid Synthesis ◽  
Liver X Receptor ◽  
Cholesterol Homeostasis ◽  
Type I Interferons ◽  
Type I ◽  
Liver X Receptors ◽  
Inflammatory Signals ◽  
X Receptors

ABSTRACT Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.

Liver X receptors in immune cell function in humans

2015 ◽  
Vol 43 (4) ◽  
pp. 752-757 ◽  
Author(s):  
Kirsty E. Waddington ◽  
Elizabeth C. Jury ◽  
Inés Pineda-Torra
Keyword(s):  
Lipid Metabolism ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Inflammatory Stimuli ◽  
X Receptors ◽  
Species Specific

The liver X receptors (LXRs), LXRα and LXRβ, are transcription factors with well-established roles in the regulation of lipid metabolism and cholesterol homeostasis. In addition, LXRs influence innate and adaptive immunity, including responses to inflammatory stimuli, proliferation and differentiation, migration, apoptosis and survival. However, the majority of work describing the role of LXRs in immune cells has been carried out in mouse models, and there are a number of known species-specific differences concerning LXR function. Here we review what is known about the role of LXRs in human immune cells, demonstrating the importance of these receptors in the integration of lipid metabolism and immune function, but also highlighting the need for a better understanding of the species, isoform, and cell-type specific effects of LXR activation.

scholarly journals Minireview: Liver X Receptor β: Emerging Roles in Physiology and Diseases

2009 ◽  
Vol 23 (2) ◽  
pp. 129-136 ◽  
Author(s):  
Chiara Gabbi ◽  
Margaret Warner ◽  
Jan-Åke Gustafsson
Keyword(s):  
Current Knowledge ◽  
Large Family ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver X Receptors ◽  
Cholesterol Accumulation ◽  
Reverse Transport ◽  
X Receptors ◽  
Lateral Sclerosis

Abstract Liver X receptors, LXRα and LXRβ, are nuclear receptors belonging to the large family of transcription factors. After activation by oxysterols, LXRs play a central role in the control of lipid and carbohydrate metabolism as well as inflammation. The role of LXRα has been extensively studied, particularly in the liver and macrophages. In the liver it prevents cholesterol accumulation by increasing bile acid synthesis and secretion into the bile through ATP-binding cassette G5/G8 transporters, whereas in macrophages it increases cholesterol reverse transport. The function of LXRβ is still under investigation with most of the current knowledge coming from the study of phenotypes of LXRβ−/− mice. With these mice new emerging roles for LXRβ have been demonstrated in the pathogenesis of diseases such as amyotrophic lateral sclerosis and chronic pancreatitis. The present review will focus on the abnormalities described so far in LXRβ−/− mice and the insight gained into the possible roles of LXRβ in human diseases.

scholarly journals Regulation of Cholesterol Homeostasis and Lipid Metabolism in Skeletal Muscle by Liver X Receptors

2002 ◽  
Vol 277 (43) ◽  
pp. 40722-40728 ◽  
Author(s):  
George E. O. Muscat ◽  
Brandee L. Wagner ◽  
Jinzhao Hou ◽  
Rajendra K. Tangirala ◽  
Eric D. Bischoff ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
X Receptors

scholarly journals Prostate Cancer Stimulation by a Novel Liver X Receptor (LXRa)-Estrogen Related Receptor (ERRa) Axis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1030-A1030
Author(s):  
Chung Seog Song ◽  
Bandana Chatterjee
Keyword(s):  
Prostate Cancer ◽  
Cell Function ◽  
Immune Cell ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Blood Cholesterol ◽  
Upstream Region ◽  
Clinical Samples ◽  
Cell Models ◽  
Genetic Ablation

Abstract Background: Liver X Receptors (LXRα, β) are oxysterol sensing nuclear receptors that regulate lipogenesis, cholesterol homeostasis and immune cell function. While oxysterols are agonist ligands of LXRs, sulfated oxysterols, catalytically produced by the SULT2B1b sulfotransferase, are LXR-inert. Increased SULT2B1b expression leads to attenuation of LXR signaling. In a previous report, we showed that SULT2B1b is undetectable in clinical samples of castration-resistant prostate cancer (CRPC), and its level is significantly reduced in a subset of primary prostate cancer. In cell models, genetic ablation of SULT2B1b exacerbated aggressive traits of CRPC, evident from EMT-like activation, enhanced invasion, faster xenograft tumor growth and reduced cell adhesiveness and stiffness in single-cell atomic force microscopy analysis. AKR1C3, which promotes androgen biosynthesis and shows elevated expression in advanced prostate cancer, is markedly upregulated in SULT2B-depleted cells. Elevated AKR1C3 leads to activation of the ERK1/2 Map kinase survival signal in CRPC cells. Results: We report here that AKR1C3 upregulation is a consequence of enhanced LXRα signaling in SULT2B1b-deficient cells, since the upregulation was abolished in multiple cell models when LXRα was silenced by siRNAs or inactivated by the small molecule inhibitor SR9243, which is an LXRs-selective inverse agonist. Conversely, LXR agonism induced by an oxysterol, or by the synthetic ligand GW3965, resulted in elevated AKR1C3 expression. Consistent with a recent report that the nuclear receptor ERRα is a positive regulator of AKR1C3, we found that ERRα ablation prevented AKR1C3 upregulation in SULT2B1b-deficient cells. Notably, LXRα inactivation caused marked reduction of ERRα, indicating that ERRα functions downstream of LXRα to induce AKR1C3 and ERK1/2. Dependence of ERRα and AKR1C3 expression on LXRα was observed in both androgen receptor (AR)-positive and AR-negative CRPC cells. Elevated ERRα in prostate cancer is known to be associated with a poor disease outcome. This association may be in part due to ERRα activation by cholesterol, which is the endogenous agonist ligand for ERRα (Cell Metab 23: 479, 2016), and high cholesterol is a risk factor for aggressive prostate cancer. Furthermore, statins, which inhibit cholesterol biosynthesis, are beneficial to CRPC patients with elevated blood cholesterol. We identified two cholesterol-responsive ERRα-binding sites in the far upstream region of the AKR1C3 promoter. This result confirms that ERRα plays a direct role in the transcriptional upregulation of AKR1C3. Significance: Our study establishes a novel LXRα→ERRα→AKR1C3→ERK1/2 survival axis that is activated in CRPC cells under SULT2B1b deficiency. The LXRα→ERRα regulatory axis may be exploited for developing novel therapeutics against AR-positive and AR-negative CRPC.

Sensing Nuclear Glucose

2007 ◽  
Vol 2007 (369) ◽  
pp. tw20-tw20
Author(s):  
Elizabeth M. Adler
Keyword(s):  
Lipid Metabolism ◽  
Transcriptional Activation ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Glucose Sensor ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Binding Domains ◽  
Glucose And Lipid Metabolism ◽  
X Receptors

The liver X receptors (LXR-α and -β) are nuclear transcription factors that have been implicated in both glucose and lipid metabolism; their activation by oxysterol ligands elicits both a decrease in atherosclerosis and antidiabetic effects. Although synthetic LXR ligands decrease hepatic gluconeogenesis and increase lipogenesis in rodent models, the normal rodent diet lacks cholesterol, which led Mitro et al. to search for other ligands. They found that glucose and glucose derivatives stimulated the transcriptional activation of a Gal4-responsive gene reporter in human HepG2 cells expressing constructs in which LXR ligand-binding domains (LBDs) were fused to the Gal4 DNA binding domain and transcriptionally activated LXR-RXR (retinoid X receptor) targets. Cell-free coactivator recruitment assays and scintillation proximity assays indicated that glucose and glucose-6-phosphate were direct LXR agonists that bound to the LXR LBD. Furthermore, glucose protected LXR-α from proteolytic attack and increased the LXR-β melting temperature. Glucose had effects on the transcription of LXR target genes in HEPG2 cells similar to those of known ligands, stimulating the expression of genes involved in fatty acid synthesis and cholesterol homeostasis and inhibiting expression of gluconeogenic genes; moreover, it potentiated the effects of LXR ligands. Similarly, glucose- or sucrose-feeding stimulated the expression of LXR target genes in the livers of fasted mice, even mice that were insulin deficient. Thus, glucose itself appears to act as a ligand for LXR, leading the authors to propose that LXR acts as a "transcriptional switch" to coordinate carbohydrate and lipid metabolism. N. Mitro, P. A. Mak, L. Vargas, C. Godio, E. Hampton, V. Molteni, A. Kreusch, E. Saez, The nuclear receptor LXR is a glucose sensor. Nature445, 219-223 (2007). [PubMed]

scholarly journals Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB Mice

2003 ◽  
Vol 197 (6) ◽  
pp. 777-788 ◽  
Author(s):  
Marie-Laure Santiago-Raber ◽  
Roberto Baccala ◽  
Katarina M. Haraldsson ◽  
Divaker Choubey ◽  
Timothy A. Stewart ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Indirect Evidence ◽  
Dendritic Cell Maturation ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifns ◽  
Common Receptor

Indirect evidence suggests that type-I interferons (IFN-α/β) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-α/βR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.

scholarly journals Liver X Receptors Interact with Corepressors to Regulate Gene Expression

2003 ◽  
Vol 17 (6) ◽  
pp. 1019-1026 ◽  
Author(s):  
Xiao Hu ◽  
Suzhen Li ◽  
Jun Wu ◽  
Chunsheng Xia ◽  
Deepak S. Lala
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Target Gene ◽  
Critical Role ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Regulate Gene Expression ◽  
Target Gene Expression ◽  
X Receptors ◽  
Regulate Gene

Abstract Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate gene expression in response to oxysterols and play a critical role in cholesterol homeostasis by regulating genes that are involved in cholesterol transport, catabolism, and triglyceride synthesis. Oxysterols and synthetic agonists bind LXRs and activate transcription by recruiting coactivator proteins. The role of LXRs in regulating target gene expression in the absence of ligand is unknown. Here we show that LXRs interact with corepressors, N-CoR (nuclear receptor corepressor) and SMRT (silent mediator of retinoic acid receptor and thyroid receptor), which are released upon binding agonists. The LXR-corepressor interaction is isoform selective, wherein LXRα has a very strong interaction with corepressors and LXRβ only shows weak interaction. LXRs also exhibit a preference for interacting with N-CoR vs. SMRT. Similar to other nuclear receptors, mutations in the LXR helix 3 and 4 region abolish corepressor interaction. Using a transient transfection assay, we demonstrate that LXR represses transcription that can be further increased by cotransfecting N-CoR into cells. Chromatin immunoprecipitation experiments further indicated that N-CoR is recruited onto endogenous LXR target genes, and addition of LXR agonists releases N-CoR from their promoters. Collectively, these results suggest that corepressors play an important role in regulating LXR target gene expression.

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