Role of liver X receptors in cholesterol efflux and inflammatory signaling (Review)

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.

Download Full-text

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

PLoS Biology ◽

10.1371/journal.pbio.3000948 ◽

2020 ◽

Vol 18 (12) ◽

pp. e3000948

Author(s):

Laura Bousset ◽

Amandine Septier ◽

Julio Bunay ◽

Allison Voisin ◽

Rachel Guiton ◽

...

Keyword(s):

Chronic Inflammation ◽

Nuclear Receptors ◽

Metabolic Disorders ◽

Androgen Deprivation ◽

Liver X Receptors ◽

Phenotypic Alteration ◽

Prostate Cells ◽

Common Causes ◽

X Receptors

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

Download Full-text

On the role of estrogen receptors and liver X receptors (LXRs) in lipid metabolism

10.1240/sav_gbm_2004_m_000510 ◽

2004 ◽

Vol 2004 (Spring) ◽

Author(s):

Jan-�ke Gustafsson

Keyword(s):

Lipid Metabolism ◽

Estrogen Receptors ◽

Liver X Receptors ◽

X Receptors

Download Full-text

Elucidating the role of Liver X receptors (LXRs) in the testis using lipid systems biology

Endocrine Abstracts ◽

10.1530/endoabs.49.oc3.2 ◽

2017 ◽

Author(s):

Sheba Jarvis ◽

Lee Gethings ◽

Raffaella Gadaleta ◽

Lord Robert Winston ◽

Catherine Williamson ◽

...

Keyword(s):

Systems Biology ◽

Liver X Receptors ◽

X Receptors

Download Full-text

Lipid metabolism as a mechanism of immunomodulation in macrophages: the role of liver X receptors

Current Opinion in Pharmacology ◽

10.1016/j.coph.2020.02.003 ◽

2020 ◽

Vol 53 ◽

pp. 18-26 ◽

Cited By ~ 5

Author(s):

Sophia Leussink ◽

Irene Aranda-Pardos ◽

Noelia A-Gonzalez

Keyword(s):

Lipid Metabolism ◽

Liver X Receptors ◽

X Receptors

Download Full-text

Liver X Receptors and Their Implications in the Physiology and Pathology of the Peripheral Nervous System

International Journal of Molecular Sciences ◽

10.3390/ijms20174192 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4192

Author(s):

Venkat Krishnan Sundaram ◽

Charbel Massaad ◽

Julien Grenier

Keyword(s):

Nervous System ◽

Peripheral Nervous System ◽

Sensory Neurons ◽

Peripheral Nerves ◽

Therapeutic Potential ◽

Positive Impact ◽

Redox Homeostasis ◽

Liver X Receptors ◽

X Receptors

Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System.

Download Full-text

LXRβ is the dominant LXR subtype in skeletal muscle regulating lipogenesis and cholesterol efflux

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00553.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. E602-E613 ◽

Cited By ~ 20

Author(s):

N. P. Hessvik ◽

M. V. Boekschoten ◽

M. A. Baltzersen ◽

S. Kersten ◽

X. Xu ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Cholesterol Efflux ◽

Target Genes ◽

Cholesterol Metabolism ◽

Receptor Subtypes ◽

Mrna Levels ◽

Functional Studies ◽

X Receptors

Liver X receptors (LXRs) are important regulators of cholesterol, lipid, and glucose metabolism and have been extensively studied in liver, macrophages, and adipose tissue. However, their role in skeletal muscle is poorly studied and the functional role of each of the LXRα and LXRβ subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild-type (WT) and LXRα and LXRβ knockout (KO) mice were established. The present study showed that treatment with the LXR agonist T0901317 increased lipogenesis and apoA1-dependent cholesterol efflux in LXRα KO and WT myotubes but not in LXRβ KO cells. The functional studies were confirmed by T0901317-induced increase in mRNA levels of LXR target genes involved in lipid and cholesterol metabolism in myotubes established from WT and LXRα KO mice, whereas only minor changes were observed for these genes in myotubes from LXRβ KO mice. Gene expression analysis using microarrays showed that very few genes other than the classical, well-known LXR target genes were regulated by LXR in skeletal muscle. The present study also showed that basal glucose uptake was increased in LXRβ KO myotubes compared with WT myotubes, suggesting a role for LXRβ in glucose metabolism in skeletal muscle. In conclusion, LXRβ seems to be the main LXR subtype regulating lipogenesis and cholesterol efflux in skeletal muscle.

Download Full-text