The LXRs: a new class of oxysterol receptors

doi:10.1016/S0959-437X(98)80013-0

Current Opinion in Genetics & Development

Volume 8, Issue 5, October 1998, Pages 571-575

https://doi.org/10.1016/S0959-437X(98)80013-0 Get rights and content

Abstract

The liver X receptors (LXRs) are a family of transcription factors that were first identified as orphan members of the nuclear receptor superfamily. The identification of a specific class of oxidized derivatives of cholesterol as ligands for the LXRs has been crucial to helping understand the function of these receptors in vivo and first suggested their role in the regulation of lipid metabolism. Confirmation of this role has come from the recent analysis of LXR-deficient mice, which has demonstrated the essential function of one of these receptors in the liver as a major sensor of dietary cholesterol.

References (37)

DJ Mangelsdorf et al.
The nuclear receptor superfamily: the second decade
Cell
(1995)
M Beato et al.
Steroid hormone receptors: many actors in search of a plot
Cell
(1995)
P Kastner et al.
Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life?
Cell
(1995)
CS Thummel
From embryogenesis to metamorphosis: The regulation and function of Drosophila nuclear receptor superfamily members
Cell
(1995)
PJ Willy et al.
Nuclear orphan receptors: the search for novel ligands and signaling pathways
M Teboul et al.
OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor
Proc Natl Acad Sci USA
(1995)
BM Forman et al.
Unique response pathways are established by allosteric interactions among nuclear hormone receptors
Cell
(1995)
FF Wiebel et al.
Heterodimeric interaction between retinoid X receptor α and orphan nuclear receptor OR1 reveals dimerization-induced activation as a novel mechanism of nuclear receptor activation
Mol Cell Biol
(1997)
FR Taylor et al.
24,25-Epoxycholesterol metabolism in cultured mammalian cells and repression of 3-hydroxy-3-methylglutaryl-CoA reductase
J Biol Chem
(1986)
AK Dhar et al.
Biosynthesis of cholest-5-ene-3β, 24-diol (cerebrosterol) by bovine cerebral cortical microsomes
J Neurochem
(1973)

D Lütjohann et al.

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation

Proc Natl Acad Sci USA

(1996)

MS Brown et al.

The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor

Cell

(1997)

MS Brown et al.

Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol

J Biol Chem

(1974)

E Enmark et al.

Orphan nuclear receptors - The first eight years

Mol Endocrinol

(1996)

R Apfel et al.

A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily

Mol Cell Biol

(1994)

PJ Willy et al.

LXR, a nuclear receptor that defines a distinct retinoid response pathway

Genes Dev

(1995)

C Song et al.

Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors

Proc Natl Acad Sci USA

(1994)

DM Shinar et al.

NER, a new member of the gene family encoding the human steroid hormone nuclear receptor

Gene

(1994)

Cited by (327)

Unraveling the impact of 27-hydroxycholesterol in autoimmune diseases: Exploring promising therapeutic approaches
2023, Pathology Research and Practice
The role of 27-hydroxycholesterol (27-OHC) in autoimmune diseases has become a subject of intense research in recent years. This oxysterol, derived from cholesterol, has been identified as a significant player in modulating immune responses and inflammation. Its involvement in autoimmune pathogenesis has drawn attention to its potential as a therapeutic target for managing autoimmune disorders effectively. 27-OHC, an oxysterol derived from cholesterol, has emerged as a key player in modulating immune responses and inflammatory processes. It exerts its effects through various mechanisms, including activation of nuclear receptors, interaction with immune cells, and modulation of neuroinflammation. Additionally, 27-OHC has been implicated in the dysregulation of lipid metabolism, neurotoxicity, and blood-brain barrier (BBB) disruption. Understanding the intricate interplay between 27-OHC and autoimmune diseases, particularly neurodegenerative disorders, holds promise for developing targeted therapeutic strategies. Additionally, emerging evidence suggests that 27-OHC may interact with specific receptors and transcription factors, thus influencing gene expression and cellular processes in autoimmune disorders. Understanding the intricate mechanisms by which 27-OHC influences immune dysregulation and tissue damage in autoimmune diseases is crucial for developing targeted therapeutic interventions. Further investigations into the molecular pathways and signaling networks involving 27-OHC are warranted to unravel its full potential as a therapeutic target in autoimmune diseases, thereby offering new avenues for disease intervention and management.
Pharmacophore modeling for biological targets with high flexibility: LXRβ case study
2022, Medicine in Drug Discovery
Many biological targets are characterized by high binding pocket flexibility posing a challenge in identifying important ligand binding features. Liver X receptors (LXRs) are members of the nuclear hormone receptor super family. Although several X-ray structures for LXRβ bound ligands are available, differences in ligands’ binding poses and interactions in the ligand binding pocket causes a challenge in identifying general elements of ligand binding. In this study, we used several LXR X-ray structures and known LXR ligands to study how LXRβ ligands interact with the LXRβ receptor. Using this information, we generated several pharmacophore models that represents important chemical features necessary for LXR binding and activation. Our results show that generating pharmacophore models based on a combined approach of multiple ligands alignments and considering the ligands’ binding coordinates yielded the best results. The generated pharmacophore model will be useful for future ligand discovery of LXRβ modulators using virtual screening.
Targeting cholesterol homeostasis in hematopoietic malignancies
2022, Blood
Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation, and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation, and hematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis by either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials involving acute myeloid leukemia to test the combination of chemotherapy with drugs interfering with cholesterol synthesis (ie, statins). We review the role of cholesterol homeostasis in hematopoietic malignancies as well as in cells of the tumor microenvironment and discuss the potential use of lipid modulators for therapeutic purposes.
Introduction to metabolic disorders
2022, Drug Delivery Systems for Metabolic Disorders
A metabolic disorder is a disorder that negatively alters the body’s processing and distribution of macronutrients such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the normal metabolic process. It can also be defined as an inherited single gene anomaly, most of which are autosomal recessive. Some of the symptoms that can occur with metabolic disorders are lethargy, weight loss, jaundice, and seizures. The symptoms expressed would vary with the type of metabolic disorder. There are four categories of symptoms: acute symptoms, late-onset acute symptoms, progressive general symptoms, and permanent symptoms. Metabolic disorders such as Obesity, Diabetes Type 2 (T2DM), and Inflammatory Bowel Diseases are the most prevalent globally. Inherited metabolic disorders are one cause of metabolic disorders, and occur when a defective gene causes an enzyme deficiency. These diseases, of which there are many subtypes, are known as inborn errors of metabolism. Metabolic diseases can also occur when the liver or pancreas does not function properly. The present chapter gives a brief overview of the different metabolic disorders.
Regulation of cholesterol biosynthesis and lipid metabolism: A microRNA management perspective
2021, Steroids
Cellular disruption of lipid and cholesterol metabolism results in pathological processes linked to metabolic and cardiovascular diseases. Classically, at the transcription stages, the Cholesterol levels are controlled by two cellular pathways. First, the SREBP transcription factor family controls Cholesterol biosynthesis via transcriptional regulation of critical rate-limiting cholesterogenic and lipogenic proteins. Secondly, The LXR/RXR transcription factor family controls cholesterol shuttling via transcriptional regulation of cholesterol transport proteins. In addition, the posttranscriptional control of gene expression of various enzymes and proteins of cholesterol biosynthesis pathways is mediated by small non-coding microRNAs. Regulatory noncoding miRNAs are critical regulators of biological processes, including developmental and metabolic functions. miRNAs function to fine-tune lipid and cholesterol metabolism pathways by controlling the mRNA levels and translation of critical molecules in each pathway. This review discusses the regulatory roles of miRNAs in cholesterol and lipid metabolism via direct and indirect effects on their target genes, including SREBP, LXR, HDL, LDL, and ABCA transporters. We also discuss the therapeutic implications of miRNA functions and their purported role in the potentiation of small molecule therapies.
Molecular mechanism of liver X receptors in cancer therapeutics
2021, Life Sciences
Liver X receptors (LXRs) are receptors that belong to the nuclear receptor superfamily (NRs). It was originally called the “orphan receptor” when it was firstly discovered. Then it was found to be activated by oxysterol and it was officially named LXRs. LXRs are activated by ligands and bind to the retinol X receptor to form a heterodimer and regulate metabolism. Numerous studies have shown that LXRs are involved in regulating immune function and maintaining immune tolerance. Activating LXRs can also inhibit the tumorigenesis and promote apoptosis of tumor cells, which make LXRs as potential targets in cancer treatment. This review will discuss the recent progress of LXRs from the structure and function of LXRs, the signaling pathway of LXRs, the molecular mechanism of LXRs activation in cancers, and the potential targets of LXRs in cancer therapy.

View all citing articles on Scopus

¹: Davo.mango@email:swmed.edu

View full text

The LXRs: a new class of oxysterol receptors

Abstract

Cell

Cell

Cell

Cell

Proc Natl Acad Sci USA

Cell

Mol Cell Biol

J Biol Chem

J Neurochem

Proc Natl Acad Sci USA

Cell

J Biol Chem

Orphan nuclear receptors - The first eight years

Mol Endocrinol

A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily

Mol Cell Biol

LXR, a nuclear receptor that defines a distinct retinoid response pathway

Genes Dev

Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors

Proc Natl Acad Sci USA

NER, a new member of the gene family encoding the human steroid hormone nuclear receptor

Gene