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Article ; Online: An optimized protocol with a stepwise approach to identify specific nuclear receptor ligands from cultured mammalian cells

Alexandre Berthier / Bart Staels / Philippe Lefebvre

STAR Protocols, Vol 2, Iss 3, Pp 100658- (2021)

2021

Abstract: Summary: Here, we describe an optimized protocol to identify specific nuclear receptor ligands. First, to rule out any compound interference with luciferase activity per se, we describe an in vitro assay assessing potential inhibition or activation of ... ...

Abstract	Summary: Here, we describe an optimized protocol to identify specific nuclear receptor ligands. First, to rule out any compound interference with luciferase activity per se, we describe an in vitro assay assessing potential inhibition or activation of luciferase enzymatic activity. Second, to comply with EMA and FDA guidelines to mitigate drug-drug interactions, we detail assays assessing constitutive androstane receptor (CAR) and pregnane X receptor (PXR) activation ability. Finally, to minimize off-target detection effects, we describe the use of mammalian one- (or two-) hybrid systems.For complete details on the use and execution of this protocol, please refer to Hering et al. (2018).
Keywords	Cell Biology ; Cell-based Assays ; High Throughput Screening ; Molecular Biology ; Science (General) ; Q1-390
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Anthropophanies. Est-il possible de voir un être humain ? Lectures bibliques

Philippe Lefebvre

Pallas, Vol 92, Pp 273-

2013 Volume 287

Abstract: In the Bible, seeing God is claimed to be impossible for humans; yet some testify that they did see him and God himself condescends to let himself be seen. Conversely, is it sure that humans can be seen? It seems self-evident that they can be seen, and ... ...

Abstract	In the Bible, seeing God is claimed to be impossible for humans; yet some testify that they did see him and God himself condescends to let himself be seen. Conversely, is it sure that humans can be seen? It seems self-evident that they can be seen, and yet…Full many characters that the biblical text sets before our eyes are people whom no one usually notices. The text educates our sight in order that we may take into account the maidservant who sees God or the nobody who will soon be a messiah. Certain scenes are real anthropophanies: in full light, a man, a woman appears in his/her reality and unnoticed glory.
Keywords	Bible ; seeing ; being seen ; look ; Hagar ; Jacob ; Social Sciences ; H
Language	French
Publishing date	2013-04-01T00:00:00Z
Publisher	Presses universitaires du Midi
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology

Vanessa Dubois / Bart Staels / Philippe Lefebvre / Michael P. Verzi / Jérôme Eeckhoute

Cells, Vol 9, Iss 2185, p

2020 Volume 2185

Abstract: Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor family whose expression and activities are restricted to a limited number of organs including the liver and gastrointestinal tract. In this review, we ... ...

Abstract	Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor family whose expression and activities are restricted to a limited number of organs including the liver and gastrointestinal tract. In this review, we present robust evidence pointing to HNF4 as a master regulator of cellular differentiation during development and a safekeeper of acquired cell identity in adult organs. Importantly, we discuss that transient loss of HNF4 may represent a protective mechanism upon acute organ injury, while prolonged impairment of HNF4 activities could contribute to organ dysfunction. In this context, we describe in detail mechanisms involved in the pathophysiological control of cell identity by HNF4, including how HNF4 works as part of cell-specific TF networks and how its expression/activities are disrupted in injured organs.
Keywords	HNF4 nuclear receptor ; cell identity ; functional genomics ; liver and gastrointestinal pathophysiology ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Control of lipid metabolism by the dynamic and nutrient‐dependent post‐translational modification O‐GlcNAcylation

Céline Schulz / Quentin Lemaire / Alexandre Berthier / Amandine Descat / Mostafa Kouach / Anne‐Sophie Vercoutter‐Edouart / Ikram El Yazidi‐Belkoura / Stéphan Hardivillé / Jean‐François Goossens / Philippe Lefebvre / Tony Lefebvre

Natural Sciences, Vol 3, Iss 2, Pp n/a-n/a (2023)

2023

Abstract: Abstract O‐GlcNAcylation is a post‐translational modification belonging to the large group of glycosylations. It consists of the modification of cytoplasmic, nuclear, and mitochondrial proteins with a single N‐acetylglucosamine residue by O‐GlcNAc ... ...

Abstract	Abstract O‐GlcNAcylation is a post‐translational modification belonging to the large group of glycosylations. It consists of the modification of cytoplasmic, nuclear, and mitochondrial proteins with a single N‐acetylglucosamine residue by O‐GlcNAc transferase (OGT). Despite its structural simplicity, O‐GlcNAcylation orchestrates many functions inside the cell. This modification regulates fatty acids synthesis, fat storage, and utilization. The generation of white and brown adipocyte‐OGT knock‐out mice has highlighted the marked interference of O‐GlcNAcylation in adiposity and, as a consequence, in metabolic pathologies. OGT is more especially involved in the regulation of lipolysis, and thermogenesis in brown adipose tissue. In addition, O‐GlcNAcylation directly regulates fatty acid synthase, the main enzyme responsible for fatty acids synthesis, and other lipogenic enzymes and transcription factors. Nevertheless, only a few studies reported connections between O‐GlcNAcylation and homeostasis of cholesterol or its derivatives. This knowledge gap is surprising due to the crucial importance of cholesterol in structuring animal biological membranes and as a precursor of a wide variety of biological compounds. Here, we review the current literature about this topic and discuss future prospects in the field. Key points As a PTM, O‐GlcNAcylation exponentially expands protein functions. O‐GlcNAcylation orchestrates many biological functions in living beings including metabolic fluxes. O‐GlcNAcylation is crucial for fat storage and mobilization, and for fatty acid synthesis but its function in the metabolism of other lipid compounds is less documented.
Keywords	lipids ; metabolism ; O‐GlcNAcylation ; Science ; Q
Subject code	571
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Wiley-VCH
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis

Hélène Dehondt / Arianna Marino / Laura Butruille / Denis A. Mogilenko / Arielle C. Nzoussi Loubota / Oscar Chávez-Talavera / Emilie Dorchies / Emmanuelle Vallez / Joel Haas / Bruno Derudas / Antonino Bongiovanni / Meryem Tardivel / Folkert Kuipers / Philippe Lefebvre / Sophie Lestavel / Anne Tailleux / David Dombrowicz / Sandrine Caron / Bart Staels

Molecular Metabolism, Vol 69, Iss , Pp 101686- (2023)

2023

Abstract: Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. ... ...

Abstract	Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. Methods: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR−/−) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR−/−) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR−/− mice. Results: eWAT from HFD-fed whole-body FXR−/− and Ad-FXR−/− mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR−/− mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR−/− mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. Conclusions: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.
Keywords	White adipose tissue ; Nuclear receptor FXR ; Inflammation ; Oxidative stress ; Glucose metabolism ; Internal medicine ; RC31-1245
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enterocyte superoxide dismutase 2 deletion drives obesity

Oihane Garcia-Irigoyen / Fabiola Bovenga / Marilidia Piglionica / Elena Piccinin / Marica Cariello / Maria Arconzo / Claudia Peres / Paola Antonia Corsetto / Angela Maria Rizzo / Marta Ballanti / Rossella Menghini / Geltrude Mingrone / Philippe Lefebvre / Bart Staels / Takuji Shirasawa / Carlo Sabbà / Gaetano Villani / Massimo Federici / Antonio Moschetta

iScience, Vol 25, Iss 1, Pp 103707- (2022)

2022

Abstract: Summary: Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here, we show that deficiency of the major mitochondrial ... ...

Abstract	Summary: Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here, we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity and inflammation via phospholipase A2 (PLA2) activation and increased release of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese phenotype was rescued when fed an essential fatty acid-deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal Sod2 mRNA levels and obesity features appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal Sod2 levels, PLA2 activity, and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.
Keywords	Obesity medicine ; Lipid ; Molecular physiology ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Coordinated Regulation of PPAR Expression and Activity through Control of Chromatin Structure in Adipogenesis and Obesity

Jérôme Eeckhoute / Frédérik Oger / Bart Staels / Philippe Lefebvre

PPAR Research, Vol

2012 Volume 2012

Abstract: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is required for differentiation and function of mature adipocytes. Its expression is induced during adipogenesis where it plays a key role in establishing the transcriptome of ... ...

Abstract	The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is required for differentiation and function of mature adipocytes. Its expression is induced during adipogenesis where it plays a key role in establishing the transcriptome of terminally differentiated white fat cells. Here, we review findings indicating that PPARγ expression and activity are intricately regulated through control of chromatin structure. Hierarchical and combinatorial activation of transcription factors, noncoding RNAs, and chromatin remodelers allows for temporally controlled expression of PPARγ and its target genes through sequential chromatin remodelling. In obesity, these regulatory pathways may be altered and lead to modified PPARγ activity.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Production, Characterization, and Applications of Porous Materials

Nikolaos Michailidis / Alexander Tsouknidas / Louis-Philippe Lefebvre / Thomas Hipke / Naoyuki Kanetake

Advances in Materials Science and Engineering, Vol

2014 Volume 2014

Keywords	Physics ; QC1-999 ; Science ; Q ; Materials of engineering and construction. Mechanics of materials ; TA401-492 ; Electrical engineering. Electronics. Nuclear engineering ; TK1-9971 ; Technology ; T
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modulation of large dense core vesicle insulin content mediates rhythmic hormone release from pancreatic beta cells over the 24h cycle.

Aurore Quinault / Corinne Leloup / Geoffrey Denwood / Coralie Spiegelhalter / Marianne Rodriguez / Philippe Lefebvre / Nadia Messaddeq / Quan Zhang / Catherine Dacquet / Luc Pénicaud / Stephan C Collins

PLoS ONE, Vol 13, Iss 3, p e

2018 Volume 0193882

Abstract: The rhythmic nature of insulin secretion over the 24h cycle in pancreatic islets has been mostly investigated using transcriptomics studies showing that modulation of insulin secretion over this cycle is achieved via distal stages of insulin secretion. ... ...

Abstract	The rhythmic nature of insulin secretion over the 24h cycle in pancreatic islets has been mostly investigated using transcriptomics studies showing that modulation of insulin secretion over this cycle is achieved via distal stages of insulin secretion. We set out to measure β-cell exocytosis using in depth cell physiology techniques at several time points. In agreement with the activity and feeding pattern of nocturnal rodents, we find that C57/Bl6J islets in culture for 24h exhibit higher insulin secretion during the corresponding dark phase than in the light phase (Zeitgeber Time ZT20 and ZT8, respectively, in vivo). Glucose-induced insulin secretion is increased by 21% despite normal intracellular Ca2+ transients and depolarization-evoked exocytosis, as measured by whole-cell capacitance measurements. This paradox is explained by a 1.37-fold increase in beta cell insulin content. Ultramorphological analyses show that vesicle size and density are unaltered, demonstrating that intravesicular insulin content per granule is modulated over the 24h cycle. Proinsulin levels did not change between ZT8 and ZT20. Islet glucagon content was inversely proportional to insulin content indicating that this unique feature is likely to support a physiological role. Microarray data identified the differential expression of 301 transcripts, of which 26 are miRNAs and 54 are known genes (including C2cd4b, a gene previously involved in insulin processing, and clock genes such as Bmal1 and Rev-erbα). Mouse β-cell secretion over the full course of the 24h cycle may rely on several distinct cellular functions but late night increase in insulin secretion depends solely on granule insulin content.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients

Daniel Margerie / Philippe Lefebvre / Violeta Raverdy / Uwe Schwahn / Hartmut Ruetten / Philip Larsen / Alain Duhamel / Julien Labreuche / Dorothée Thuillier / Bruno Derudas / Céline Gheeraert / Hélène Dehondt / Quentin Dhalluin / Jérémy Alexandre / Robert Caiazzo / Pamela Nesslany / Helene Verkindt / François Pattou / Bart Staels

BMC Medical Genomics, Vol 12, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract Background Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular ... ...

Abstract	Abstract Background Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. Methods An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. Results We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60–4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. Conclusions A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus ...
Keywords	Statin ; Human ; Liver ; Iatrogenic diabetes ; Gene expression ; Gene networks ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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