LXRα and LXRβ nuclear receptors evolved in the common ancestor of gnathostomes

Fonseca, Elza; Ruivo, Raquel; Lopes-Marques, Mónica; Zhang, Huixian; Santos, Miguel M.; Venkatesh, Byrappa; Castro, L. Filipe C.

doi:10.1093/gbe/evw305

Cited by 11 publications

(19 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because previous studies used cell lines with uneven levels of LXRs or antibodies that do not discriminate between LXR␣ and LXR␤, we believe that our data sets represent the most accurate LXR binding repertoire described for macrophages (4,26,27). Recently, it was reported that LXR genes arose through a gene duplication event (50). However, it is unclear whether LXR␣ has acquired specialized functions related to lipid metabolism and immunity, losing its ability to regulate other genes, or whether an expansion of LXR␤-associated functions has occurred, resulting in LXR␣ occupying a reduced number of genomic sites in comparison.…”

Section: Discussionmentioning

confidence: 99%

Common and Differential Transcriptional Actions of Nuclear Receptors Liver X Receptors α and β in Macrophages

Ramón-Vázquez

Rosa

Tabraue

et al. 2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

The liver X receptors α and β (LXRα and LXRβ) are oxysterol-activated transcription factors that coordinately regulate gene expression that is important for cholesterol and fatty acid metabolism. In addition to their roles in lipid metabolism, LXRs participate in the transcriptional regulation of macrophage activation and are considered potent regulators of inflammation. LXRs are highly similar, and despite notable exceptions, most of their reported functions are substantially overlapping. However, their individual genomic distribution and transcriptional capacities have not been characterized. Here, we report a macrophage cellular model expressing equivalent levels of tagged LXRs. Analysis of data from chromatin immunoprecipitation coupled with deep sequencing revealed that LXRα and LXRβ occupy both overlapping and exclusive genomic regulatory sites of target genes and also control the transcription of a receptor-exclusive set of genes. Analysis of genomic H3K27 acetylation and mRNA transcriptional changes in response to synthetic agonist or antagonist treatments revealed a putative mode of pharmacologically independent regulation of transcription. Integration of microarray and sequencing data enabled the description of three possible mechanisms of LXR transcriptional activation. Together, these results contribute to our understanding of the common and differential genomic actions of LXRs and their impact on biological processes in macrophages.

show abstract

Section: Discussionmentioning

confidence: 99%

Common and Differential Transcriptional Actions of Nuclear Receptors Liver X Receptors α and β in Macrophages

Ramón-Vázquez

Rosa

Tabraue

et al. 2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Amphioxus possesses 10 paralogues of the FXR/LXR (Farnesoid X Receptor/Liver X Receptor) subfamily due to a lineage-specific duplication event (Lecroisey et al, 2012, Schubert et al, 2008, with one of them being a clear orthologue of vertebrate LXR. Phylogenetic approaches only clarified the orthology of 5 of the other receptors with vertebrate FXRs (Fonseca et al, 2017). Ligand binding has been characterized using transient transactivation assays for the amphioxus LXR with four different ligands (the synthetic molecule T0901317, and the natural ligands 24(S)-hydroxycholesterol, 25-hydroxycholesterol and 24(S),25epoxycholesterol).…”

Section: Cell-cell Communication Pathways In Amphioxus 707mentioning

confidence: 99%

“…Ligand binding has been characterized using transient transactivation assays for the amphioxus LXR with four different ligands (the synthetic molecule T0901317, and the natural ligands 24(S)-hydroxycholesterol, 25-hydroxycholesterol and 24(S),25epoxycholesterol). While the amphioxus LXR is able to bind and transactivate a reporter gene in the presence of these ligands, it shows a low binding affinity for them compared with its vertebrate orthologues (Fonseca et al, 2017).…”

Section: Cell-cell Communication Pathways In Amphioxus 707mentioning

confidence: 99%

Developmental cell-cell communication pathways in the cephalochordate amphioxus: actors and functions

Bertrand¹,

Pétillon²,

Somorjai³

et al. 2017

Int. J. Dev. Biol.

View full text Add to dashboard Cite

During embryonic development, cells of metazoan embryos need to communicate in order to construct the correct bodyplan. To do so, they use several signals that usually act through interactions between ligands and receptors. Interestingly, only a few pathways are known to be fundamental during animal development, and they are usually found in all the major metazoan clades, raising the following question: how have evolution of the actors and of the functions of these pathways participated in the appearance of the current diversity of animal morphologies? The chordate lineage comprises vertebrates, their sister group the urochordates, and the cephalochordates (i.e. amphioxus). Urochordates are quite derived relative to the chordate ancestor, whereas cephalochordates and vertebrates share many morphological traits. Thus, comparing embryonic development between vertebrates and cephalochordates should give us some insight into the ancestral characters present in chordates and into the morphological evolution in this clade. However, while much is known about the function of different signalling pathways in vertebrates, data are still scarce in the literature for cephalochordates. In this review, we summarize the current state of the field concerning the expression of actors and the function of the major cell-cell communication pathways, including Hedgehog (Hh), Notch, Nuclear Receptor (NR), Receptor Tyrosine Kinase (RTK), Transforming Growth Factor-β (TGF-β) and Wingless/Int (Wnt), in amphioxus.

show abstract

“…The Lxrβ locus was lost in the fish phylum (Fonseca et al, 2017). Furthermore, zebrafish Lxrα binds and is activated by endogenous and synthetic ligands in a manner similar to human LXRα (Archer et al, 2008; Reschly et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

2017

View full text Add to dashboard Cite

Post-prandial hyperlipidemia has emerged as a cardiovascular risk factor with limited therapeutic options. The Liver X receptors (Lxrs) are nuclear hormone receptors that regulate cholesterol elimination. Knowledge of their role in regulating the absorption and handling of dietary fats is incomplete. The purpose of this study was to determine the role of intestinal Lxrα in post-prandial intestinal lipid transport. Using Lxrα knockout (nr1h3−/−) and intestine-limited Lxrα over-expressing [Tg(fabp2a:EGFP-nr1h3)] zebrafish strains, we measured post-prandial lipid excursion with live imaging in larvae and physiological methods in adults. We also conducted a long-term high-cholesterol dietary challenge in adults to examine the chronic effect of modulating nr1h3 gene dose on the development of hypercholesterolemia and hepatic lipid accumulation. Over-expression of Lxrα in the intestine delays the transport of ingested lipids in larvae, while deletion of Lxrα increases the rate of lipid transport. Pre-treating wildtype larvae with the liver-sparing Lxr agonist hyodeoxycholic acid also delayed the rate of intestinal lipid transport in larvae. In adult males, deletion of Lxrα accelerates intestinal transport of ingested lipids. Adult females showed higher plasma Lipoprotein lipase (Lpl) activity compared to males, and lower post-gavage blood triacylglycerol (TAG) excursion. Despite the sexually dimorphic effect on acute intestinal lipid handling, Tg(fabp2a:EGFP-nr1h3) adults of both sexes are protected from high cholesterol diet (HCD)-induced hepatic lipid accumulation, while nr1h3−/− mutants are sensitive to the effects of HCD challenge. These data indicate that intestinal Lxr activity dampens the pace of intestinal lipid transport cell-autonomously. Selective activation of intestinal Lxrα holds therapeutic promise.

show abstract

LXRα and LXRβ nuclear receptors evolved in the common ancestor of gnathostomes

Cited by 11 publications

References 34 publications

Common and Differential Transcriptional Actions of Nuclear Receptors Liver X Receptors α and β in Macrophages

Common and Differential Transcriptional Actions of Nuclear Receptors Liver X Receptors α and β in Macrophages

Developmental cell-cell communication pathways in the cephalochordate amphioxus: actors and functions

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

Contact Info

Product

Resources

About