P1941The nuclear receptor corepressor 1 blocks CD36-mediated foam cell formation in atherogenesis

Abstract Background Nuclear receptors and their cofactors regulate the expression of various target genes in different tissue and organs to orchestrate downstream (patho)physiological processes. Although the function of several nuclear receptors in atherosclerosis has been studied, very little is known about the role of nuclear receptor cofactors in atherosclerosis. Given its important role to suppress inflammatory processes, we speculated that macrophage nuclear receptor corepressor 1 (NCOR1) plays a protective function in atherosclerosis development. Purpose To evaluate the contribution of macrophage NCOR1 in atherosclerosis we used myeloid cell-specific Ncor1 knockout mice on an atherosclerosis-prone background. Methods and results 8-week-old male and female mice were exposed to a high high-cholesterol diet for 12 weeks. Our findings demonstrate that the lack of macrophage Ncor1 leads to a severe atherosclerotic phenotype in both sexes. These mice show a higher content of plaques along the thoraco-abdominal aortae as well as at the aortic sinus, which were characterized by larger necrotic cores and thinner fibrous caps, a typical signature of unstable plaques. Moreover, we found that the pro-atherogenic effects of the Ncor1 deletion are mediated via derepression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, especially the enhanced expression of the CD36 scavenger receptor and the subsequent rise in oxLDL uptake. Interestingly, while the expression of NCOR1 is reduced, the PPARγ signature is increased in human atherosclerotic plaques, and this signature is further pronounced in ruptured compared to stable carotid plaques. Conclusion Our findings suggest that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and prevents the disease development. Acknowledgement/Funding The Swiss National Science Foundation, the Novartis Foundation, Olga-Mayenfisch Foundation, the OPO foundation

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Abstract 43: Activation of the Nuclear Receptor Coactivator PGC-1α Mediates an Atheroprotective Effect

Circulation Research ◽

10.1161/res.111.suppl_1.a43 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Cathal McCarthy ◽

Declan Mooney ◽

Monica de Gaetano ◽

William James ◽

Desmond J Fitzgerald ◽

...

Keyword(s):

Nuclear Receptor ◽

Target Genes ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Nuclear Receptor Coactivator ◽

Hub Gene ◽

Cd36 Expression ◽

Ppar Agonists ◽

Human Atherosclerosis

Supplementing dietary chow with conjugated linoleic acid (CLA) induces marked regression of pre-established murine atherosclerosis, in contrast to other PPAR agonists. The finding suggests that there are unidentified endogenous pathways that suppress the progression or promote the regression of atherosclerosis. Identifying these pathways in the mouse and their homologues in humans may help elucidate the mechanisms of the disease and targets for future therapies. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor co-activator, PGC-1α in a manner that differs from PPAR activation. Gene expression analysis was performed in the aorta of ApoE -/- mice following induction of atherosclerosis and dietary supplementation with/without CLA. CLA induced dramatic regression of the cholesterol-induced atherosclerosis. PGC-1α was identified as a ‘hub’ gene within a cluster of genes induced by CLA in the aorta of the ApoE -/- during regression. PGC-1α protein was also found in murine and human atherosclerotic plaque, where it was localised to macrophage/foam cells. In a mouse macrophage cell line exposed to oxLDL, CLA induced PGC-1α and several genes in the network in an isomer specific fashion, including RORαand ABCA1. CLA also induced the PGC-1α target genes Cyp7b1 and UCP-1, and PPAR. CLA inhibited foam cell formation in the same cells exposed to oxLDL and suppressed the expression of the scavenger receptors, SRA-1 and CD36. Expression of the PGC-1α in macrophages had similar effects. Thus, over-expression of PGC-1α limited the accumulation of oxLDL and subsequent foam cell formation, while deletion of the gene promoted foam cell formation in bone marrow derived macrophages upon exposure to oxLDL. Moreover, deletion of PGC-1α prevented the inhibition of macrophages/foam cell formation by CLA. The nuclear receptor co-activator PGC-1α is a hub gene in a network of genes activated in the aorta during CLA-induced regression of atherosclerosis and mediates CLA’s inhibition of foam cell formation. PGC-1α is also is also expressed in human plaques where its expression is inversely associated with disease progression, raising the possibility that this pathway if activated could regulate human atherosclerosis.

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The Nuclear Receptor-Coactivator Interaction Surface as a Target for Peptide Antagonists of the Peroxisome Proliferator-Activated Receptors

Molecular Endocrinology ◽

10.1210/me.2007-0201 ◽

2007 ◽

Vol 21 (10) ◽

pp. 2361-2377 ◽

Cited By ~ 32

Author(s):

Niharika B. Mettu ◽

Thomas B. Stanley ◽

Mary A. Dwyer ◽

Michelle S. Jansen ◽

John E. Allen ◽

...

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Target Genes ◽

Binding Motif ◽

Peroxisome Proliferator ◽

Constitutive Activity ◽

Phage Display Technology ◽

Nuclear Receptor Coactivator ◽

Peroxisome Proliferator Activated Receptors ◽

Interaction Surface

Abstract The peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ) constitute a family of nuclear receptors that regulates metabolic processes involved in lipid and glucose homeostasis. Although generally considered to function as ligand-regulated receptors, all three PPARs exhibit a high level of constitutive activity that may result from their stimulation by intracellularly produced endogenous ligands. Consequently, complete inhibition of PPAR signaling requires the development of inverse agonists. However, the currently available small molecule antagonists for the PPARs function only as partial agonists, or their efficacy is not sufficient to inhibit the constitutive activity of these receptors. Due to the lack of efficacious antagonists that interact with the ligand-binding domain of the PPARs, we decided to target an interaction that is central to nuclear receptor-mediated gene transcription: the nuclear receptor-coactivator interaction. We utilized phage display technology to identify short LXXLL-containing peptides that bind to the PPARs. Analysis of these peptides revealed a consensus binding motif consisting of HPLLXXLL. Cross-screening of these peptides for binding to other nuclear receptors enabled the identification of a high-affinity PPAR-selective peptide that has the ability to repress PPARγ1-dependent transcription of transfected reporter genes. Most importantly, when introduced into HepG2 cells, the peptide inhibited the expression of endogenous PPARγ1 target genes, adipose differentiation-related protein and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase 2. This work lends support for the rational development of peptidomimetics that block receptor-mediated transcription by targeting the nuclear receptor-coactivator interaction surface.

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Role of NFAT in the Progression of Diabetic Atherosclerosis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.635172 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yaoyao Cai ◽

Haipeng Yao ◽

Zhen Sun ◽

Ying Wang ◽

Yunyun Zhao ◽

...

Keyword(s):

Transcription Factor ◽

Cardiovascular System ◽

Signaling Pathways ◽

Immune Cells ◽

Target Genes ◽

Vascular System ◽

Foam Cell ◽

Vascular Diseases ◽

Regulatory Function ◽

Foam Cell Formation

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.

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Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms21239329 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9329

Author(s):

Elien Wouters ◽

Elien Grajchen ◽

Winde Jorissen ◽

Tess Dierckx ◽

Suzan Wetzels ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mononuclear Cells ◽

Foam Cell ◽

Cell Formation ◽

Autoimmune Disorder ◽

Foam Cell Formation ◽

Peroxisome Proliferator ◽

Peripheral Blood Mononuclear ◽

Peroxisome Proliferator Activated Receptors ◽

Pparγ Expression

Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to determine to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-associated proinflammatory cytokines mimicked this reduction in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced reduction in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS.

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Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature

European Heart Journal ◽

10.1093/eurheartj/ehz667 ◽

2019 ◽

Cited By ~ 6

Author(s):

Sara Oppi ◽

Stefanie Nusser-Stein ◽

Przemyslaw Blyszczuk ◽

Xu Wang ◽

Anne Jomard ◽

...

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Myeloid Cell ◽

Foam Cell Formation ◽

Low Density ◽

Enhanced Expression ◽

Atherosclerosis Development

Abstract Aims Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. Methods and results We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. Conclusions Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1–PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.

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PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽

10.1155/2010/173907 ◽

2010 ◽

Vol 2010 ◽

pp. 1-16 ◽

Cited By ~ 9

Author(s):

Sean R. Pyper ◽

Navin Viswakarma ◽

Yuzhi Jia ◽

Yi-Jun Zhu ◽

Joseph D. Fondell ◽

...

Keyword(s):

Nuclear Receptor ◽

Target Genes ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Receptor Coactivator ◽

Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

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TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0905724106 ◽

2009 ◽

Vol 106 (32) ◽

pp. 13353-13358 ◽

Cited By ~ 71

Author(s):

S. Xie ◽

Y.-F. Lee ◽

E. Kim ◽

L.-M. Chen ◽

J. Ni ◽

...

Keyword(s):

Fatty Acid ◽

Nuclear Receptor ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Cd36 Expression

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Swiprosin-1 deficiency in macrophages alleviated atherogenesis

Cell Death Discovery ◽

10.1038/s41420-021-00739-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ling-Chang Tong ◽

Zhi-Bin Wang ◽

Jia-Qi Zhang ◽

Yue Wang ◽

Wei-Ye Liu ◽

...

Keyword(s):

Foam Cell ◽

Atherosclerotic Lesion ◽

Foam Cell Formation ◽

High Cholesterol Diet ◽

Atherosclerotic Plaques ◽

Inflammatory Factor ◽

Lipid Uptake ◽

Wild Type ◽

Raw264.7 Macrophages

AbstractMacrophages play a vital role in the development of atherosclerosis. Previously, we have found that swiprosin-1 was abundantly expressed in macrophages. Here, we investigated the role of swiprosin-1 expressed in macrophages in atherogenesis. Bone marrow transplantation was performed from swiprosin-1-knockout (Swp−/−) mice and age-matched ApoE−/− mice. Atherosclerotic lesion, serum lipid, and interleukin-β (IL-β) levels were detected. In vitro, the peritoneal macrophages isolated from Swp−/− and wild-type mice were stimulated with oxidized low-density lipoprotein (ox-LDL) and the macrophage of foam degree, cellular lipid content, apoptosis, inflammatory factor, migration, and autophagy were determined. Our results showed that swiprosin-1 was mainly expressed in macrophages of atherosclerotic plaques in aorta from ApoE−/− mice fed with high-cholesterol diet (HCD). The expression of swiprosin-1 in the foaming of RAW264.7 macrophages gradually increased with the increase of the concentration and time stimulated with ox-LDL. Atherosclerotic plaques, accumulation of macrophages, collagen content, serum total cholesterol, LDL, and IL-β levels were decreased in Swp−/− → ApoE−/− mice compared with Swp+/+ → ApoE−/− mice fed with HCD for 16 weeks. The macrophage foam cell formation and cellular cholesterol accumulation were reduced, while the lipid uptake and efflux increased in macrophages isolated from Swp−/− compared to wild-type mice treated with ox-LDL. Swiprosin-1 deficiency in macrophages could inhibit apoptosis, inflammation, migration, and promote autophagy. Taken together, our results demonstrated that swiprosin-1 deficiency in macrophages could alleviate the development and progression of AS. The role of swiprosin-1 may provide a promising new target for ameliorating AS.

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The nutrigenomic metabolite L‑carnitine directly modulates the activity and expression of nuclear receptors in adipocytes, liver and muscle cells

10.21203/rs.2.14505/v1 ◽

2019 ◽

Author(s):

Lorenz Förster ◽

Dominic Indra ◽

Reinhold Hofbauer

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Target Genes ◽

Muscle Cells ◽

Carnitine Deficiency ◽

Mrna Levels ◽

Carnitine Supplementation ◽

Short Term ◽

Protein Activity ◽

Expression Levels

Abstract Background: L‑carnitine is an indispensable metabolite in eukaryotic cells, which facilitates transport of long‑chain fatty acids into the mitochondrial matrix for subsequent β-oxidation and helps to safeguard the acetyl-CoA level. Additionally, L‑carnitine has been proven to exert a nutrigenomic effect, modulating the expression of numerous target genes. However, the diverging time-dependent effects of short-term and extended L‑carnitine supplementation have not been investigated in more detail yet, especially in the interplay of adipocytes, liver and muscle cells. A cell culture model with conditions of L‑carnitine deficiency and supplementation for these cell types was established to investigate the effects of L‑carnitine on key nuclear receptors and their pathways. Results: L‑carnitine deficiency as well as L‑carnitine supplementation to hepatocytes modulated protein activity of multiple nuclear receptor pathways (RAR, RXR, VDR, PPAR, HNF4, ER, LXR). On the transcriptional level, short‑term L‑carnitine supplementation initially exerted an inhibitory effect on the steady state mRNA levels of PPAR‑α, PPAR‑δ, PPAR-γ, RAR‑β , LXR‑α and RXR‑α in adipocytes, liver and muscle cells. However, extended L‑carnitine supplementation for 24 and 48 hours led to a significant upregulation of PPAR‑α and PPAR‑δ , being key regulators of lipid catabolism, thereby promoting lipolysis and β-oxidation. In addition, significant differences in transcriptional modulation were found between adipocytes, liver and muscle cells. Extended L‑carnitine administration to hepatocytes also modulated mRNA expression levels of nuclear receptor target genes CYP2R1 , ALDH1A1 , HSD11B2 , OGT and HMGCR. Conclusions: These findings show a clear nutrigenomic effect of L‑carnitine on the protein activity and expression levels of selected nuclear receptors in different tissues, promoting lipolytic gene expression as well as decreasing transcription of adipogenic and insulin-resistance linked genes. Therefore L‑carnitine supplementation obviously is a promising strategy supporting established antihyperlipidemic therapies.

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