scholarly journals Lysosome-Dependent LXR and PPARδ Activation Upon Efferocytosis in Human Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Carolina Mota ◽  
Monica Dominguez ◽  
Andreas Weigert ◽  
Ryan G. Snodgrass ◽  
Dmitry Namgaladze ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Peroxisome Proliferator ◽  
Liver X Receptors ◽  
Human Macrophages ◽  
Sterol Regulatory Element ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

Efferocytosis is critical for tissue homeostasis, as its deregulation is associated with several autoimmune pathologies. While engulfing apoptotic cells, phagocytes activate transcription factors, such as peroxisome proliferator-activated receptors (PPAR) or liver X receptors (LXR) that orchestrate metabolic, phagocytic, and inflammatory responses towards the ingested material. Coordination of these transcription factors in efferocytotic human macrophages is not fully understood. In this study, we evaluated the transcriptional profile of macrophages following the uptake of apoptotic Jurkat T cells using RNA-seq analysis. Results indicated upregulation of PPAR and LXR pathways but downregulation of sterol regulatory element-binding proteins (SREBP) target genes. Pharmacological inhibition and RNA interference pointed to LXR and PPARδ as relevant transcriptional regulators, while PPARγ did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPARδ activation also demanded an active lysosomal phospholipase A2 (PLA2G15). Pharmacological interference with LXR signaling attenuated ABCA1-dependent cholesterol efflux from efferocytotic macrophages, but suppression of inflammatory responses following efferocytosis occurred independently of LXR and PPARδ. These data provide mechanistic details on LXR and PPARδ activation in efferocytotic human macrophages.

Transcriptional regulation of macrophage cholesterol trafficking by PPARα and LXR

2006 ◽  
Vol 34 (6) ◽  
pp. 1128-1131 ◽  
Author(s):  
G. Chinetti ◽  
J.C. Fruchart ◽  
B. Staels
Keyword(s):  
Transcription Factors ◽  
Peroxisome Proliferator ◽  
Liver X Receptors ◽  
Cholesterol Trafficking ◽  
Peroxisome Proliferator Activated Receptors ◽  
Atherosclerosis Development ◽  
X Receptors ◽  
And Function ◽  
Atherosclerosis Research

PPARs (peroxisome-proliferator-activated receptors) and LXRs (liver X receptors) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Since the macrophage plays an important role in host defence and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes, including atherosclerosis. Research over the last few years has revealed important roles for PPARs and LXRs in macrophage inflammation and cholesterol homoeostasis with consequences in atherosclerosis development. This review will discuss the role of these transcription factors in the control of cholesterol trafficking in macrophages.

scholarly journals A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation

2009 ◽  
Vol 30 (5) ◽  
pp. 1182-1198 ◽  
Author(s):  
Virginie Lecomte ◽  
Emmanuelle Meugnier ◽  
Vanessa Euthine ◽  
Christine Durand ◽  
Damien Freyssenet ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Muscle Mass ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Myogenic Program

ABSTRACT The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.

scholarly journals Peroxisome Proliferator-Activated Receptors and Shock State

2006 ◽  
Vol 6 ◽  
pp. 1770-1782 ◽  
Author(s):  
Emanuela Esposito ◽  
Salvatore Cuzzocrea ◽  
Rosaria Meli
Keyword(s):  
Transcription Factors ◽  
Energy Homeostasis ◽  
Hormone Receptors ◽  
Inflammatory Responses ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Shock State ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors ◽  
Inflammatory Molecules

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. Three isotypes of PPARs have been identified: alpha, beta/delta, and gamma, encoded by different genes and distributed in various tissues. PPARs are implicated in the control of inflammatory responses and in energy homeostasis and, thus, can be defined as metabolic and anti-inflammatory transcription factors. They exert anti-inflammatory effects by inhibiting the induction of proinflammatory cytokines, adhesion molecules, and extracellular matrix proteins, or by stimulating the production of anti-inflammatory molecules. Moreover, PPARs modulate the proliferation, differentiation, and survival of immune cells. This review presents the current state of knowledge regarding the involvement of PPARs in the control of inflammatory response, and their potential therapeutic applications in several types of shock, as well as hemorrhagic, septic, and nonseptic shock.

scholarly journals The Role of PPARs in Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2367
Author(s):  
Nicole Wagner ◽  
Kay-Dietrich Wagner
Keyword(s):  
Target Genes ◽  
Peroxisome Proliferator ◽  
Downstream Target ◽  
Novel Approach ◽  
Pparγ Agonists ◽  
Cell Type Specific ◽  
Peroxisome Proliferator Activated Receptors ◽  
Specific Regulation ◽  
X Receptors

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARβ/δ in cancer. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.

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