scholarly journals Transcriptional and Posttranscriptional Control of Cholesterol Homeostasis by Liver X Receptors

2011 ◽  
Vol 76 (0) ◽  
pp. 129-137 ◽  
Author(s):  
P. Tontonoz
Keyword(s):  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Posttranscriptional Control ◽  
X Receptors

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 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.

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 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.

scholarly journals Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

2015 ◽  
Vol 112 (24) ◽  
pp. 7587-7592 ◽  
Author(s):  
Delphine Meffre ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Mehdi Hichor ◽  
Victor Gorgievski ◽  
Eleni T. Tzavara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Motor Coordination ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Protein Levels ◽  
Myelin Sheaths ◽  
X Receptors ◽  
Myelin Gene

The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes.

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.

Regulation of cholesterol homeostasis by liver X receptors

2010 ◽  
Vol 411 (9-10) ◽  
pp. 617-625 ◽  
Author(s):  
Yan-Wei Hu ◽  
Lei Zheng ◽  
Qian Wang
Keyword(s):  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
X Receptors

scholarly journals Pathogenesis, modulation, and therapy of Alzheimer’s disease: A perspective on roles of liver-X receptors

2013 ◽  
Vol 4 (3) ◽  
Author(s):  
Jasminka Štefulj ◽  
Ute Panzenboeck ◽  
Patrick Hof ◽  
Goran Šimić
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcription Factors ◽  
Amyloid Beta ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Tau Proteins ◽  
Liver X Receptors ◽  
Proteins Metabolism ◽  
X Receptors

AbstractThe pathogenesis of Alzheimer’s disease (AD) has been mostly linked to aberrant amyloid beta (Aβ) and tau proteins metabolism, disturbed lipid/cholesterol homeostasis, and progressive neuroinflammation. Liver X receptors (LXR) are ligand-activated transcription factors, best known as the key regulators of cholesterol metabolism and transport. In addition, LXR signaling has been shown to have significant anti-inflammatory properties. In this brief review, we focus on the outcome of studies implicating LXR in the pathogenesis, modulation, and therapy of AD.

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