Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism.
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Animals↗
Biomedical subjects
T T Lu
Publications and source records attributed to T T Lu.
A coordinated change in chemokine responsiveness guides plasma cell movements.
Antibody-secreting plasma cells are nonrecirculatory and lodge in splenic red pulp, lymph node medullary cords, and bone marrow. The factors that regulate plasma cell localization are poorly defined. Here we demonstrate that, compared with their B cell precursors, plasma cells exhibit increased chemotactic sensitivity to the CXCR4 ligand CXCL12. At the same time, they downregulate CXCR5 and CCR7 and have reduced responsiveness to the B and T zone chemokines CXCL13, CCL19, and CCL21. We demonstrate that CXCL12 is expressed within splenic red pulp and lymph node medullary cords as well as in bone marrow. In chimeric mice reconstituted with CXCR4-deficient fetal liver cells, plasma cells are mislocalized in the spleen, found in elevated numbers in blood, and fail to accumulate normally in the bone marrow. Our findings indicate that as B cells differentiate into plasma cells they undergo a coordinated change in chemokine responsiveness that regulates their movements in secondary lymphoid organs and promotes lodgment within the bone marrow.
Animals↗
[Regulation of lipid metabolism by the orphan nuclear receptors].
Lipids (cholesterol and fatty acids) are essential nutriments and have a major impact on gene expression. Hence cholesterol intracellular concentration is precisely controlled by some complex mechanisms involving transcriptional regulations. The excess of cholesterol in cells is converted into oxysterols. These cholesterol metabolites are important signalisation molecules that modulate several transcription factors involved in cholesterol homeostasis. Schematically, regulation of cholesterol homeostasis is achieved by three different but complementary pathways: 1) endogeneous biosynthesis, which corresponds to the de novo synthesis of cholesterol and is controlled by sterol response element binding proteins (SREBPs); 2) the transport, intracellular absorption and esterification of the cholesterol; 3) the metabolic conversion into bile acids and steroid hormones. These three pathways are closely linked, however we will schematically detail the role of the orphan nuclear receptors on the modulation of these three levels of regulation. Phenotype analyses of knock-out or transgenic mice pointed out the respective role of the "enterohepatic" orphan nuclear receptors LXRalpha, LXRB, FXR, LRH-1, the nuclear receptor PPARalpha, and their heterodimeric partner RXR, as well as the peculiar receptor SHP. Complex feed-backs have thus been demonstrated. These transciptional regulations have several targets: the P450 cytochromes involved in the bile acid synthesis Cyp7a1 and Cyp8b1; the intestinal bile acid binding protein IBABP; the cholesteryl ester transfert protein CETP and phospholipid transfert protein PLTP, both involved in the HDL catabolism; the ABC cholesterol transporters ABCG1/ABC8 and ABCAI/ABCI. At last it seems that polyunsaturated fatty acids could activate LXRalpha transcription through its activation by PPARalpha. In the near future, the identification and study of new target genes by transcriptomic or proteomic analyses will allow a better understanding of lipid homeostasis in physiological as well as pathophysiological conditions.
Animals↗
Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.
The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1). The nuclear receptor LXRalpha binds oxysterols and mediates feed-forward induction. Here, we show that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH-1; and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH-1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results reveal an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.
Animals↗
Platelet endothelial cell adhesion molecule-1 is phosphorylatable by c-Src, binds Src-Src homology 2 domain, and exhibits immunoreceptor tyrosine-based activation motif-like properties.
Platelet endothelial cell adhesion molecule-1 (PECAM-1) is 130-kDa member of the immunoglobulin gene superfamily that localizes to cell-cell borders of confluent endothelial cells and has been shown to play a role in the control of endothelial sheet migration and leukocyte transmigration through the endothelium. The cytoplasmic tail plays an important role in the modulation of PECAM-1 function. Mutation of tyrosine 663 or 686 in the cytoplasmic tail reduces phosphorylation and mutation of 686 is associated with a reduction in PECAM-1-mediated inhibition of cell migration (1). We have previously noted that these two tyrosine residues are surrounded by consensus sequences for Src homology 2 (SH2) domain binding (1, 2), and the experiments presented explore the potential for PECAM-1-Src and PECAM-1-SH2 domain interactions. PECAM-1 is more highly phosphorylated in endothelial cells overexpressing c-Src, and in in vitro kinase assays, c-Src can phosphorylate a glutathione S-transferase (GST)-PECAM cytoplasmic tail fusion protein. The phosphorylated fusion protein associates with the bead-bound c-Src. This association appears to be mediated by Src-SH2 domain, because PECAM-1 can be precipitated by a GST-Src-SH2 affinity matrix. The binding to the GST-Src-SH2 affinity matrix correlates directly with the level of PECAM-1 phosphorylation, because more PECAM-1 is precipitated from c-Src overexpressors and from wild-type rather than Tyr663 --> Phe and Tyr686 --> Phe mutant PECAM-1 expressors. Yet unidentified phosphoproteins can also be coimmunoprecipitated with wild-type but not mutant PECAM-1. Finally, we note the similarity of the PECAM-1 cytoplasmic domain sequence to the immunoreceptor tyrosine-based activation motif. Our data begin to delineate how tyrosines 663 and 686 may play a role in mediating PECAM-1 signal transduction.
Genes, src↗
Integrin engagement mediates tyrosine dephosphorylation on platelet-endothelial cell adhesion molecule 1.
Platelet-endothelial cell adhesion molecule 1 (PECAM-1, CD31) is a 130-kDa member of the immunoglobulin gene superfamily expressed on endothelial cells, platelets, neutrophils, and monocytes and plays a role during endothelial cell migration. Phosphoamino acid analysis and Western blot analysis with anti-phosphotyrosine antibody show that endothelial PECAM-1 is tyrosine-phosphorylated. Phosphorylation is decreased with endothelial cell migration on fibronectin and collagen and with cell spreading on fibronectin but not on plastic. Cell adhesion on anti-integrin antibodies is also able to specifically induce PECAM-1 dephosphorylation while concurrently inducing pp125 focal adhesion kinase phosphorylation. Inhibition of dephosphorylation with sodium orthovanadate suggests that this effect is at least partially mediated by phosphatase activity. Tyr-663 and Tyr-686 are identified as potential phosphorylation sites and mutated to phenylalanine. When expressed, both mutants show reduced PECAM-1 phosphorylation but Phe-686 mutants also show significant reversal of PECAM-1-mediated inhibition of cell migration and do not localize PECAM-1 to cell borders. Our results suggest that beta 1-integrin engagement can signal to dephosphorylate PECAM-1 and that this signaling pathway may play a role during endothelial cell migration.
3T3 Cells↗