keyword
https://read.qxmd.com/read/33716991/dietary-fiber-is-essential-to-maintain-intestinal-size-l-cell-secretion-and-intestinal-integrity-in-mice
#21
JOURNAL ARTICLE
Jenna Elizabeth Hunt, Bolette Hartmann, Kristina Schoonjans, Jens Juul Holst, Hannelouise Kissow
Dietary fiber has been linked to improved gut health, yet the mechanisms behind this association remain poorly understood. One proposed mechanism is through its influence on the secretion of gut hormones, including glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). We aimed to: 1) investigate the impact of a fiber deficient diet on the intestinal morphological homeostasis; 2) evaluate L-cell secretion; and 3) to ascertain the role of GLP-1, GLP-2 and Takeda G protein-receptor-5 (TGR5) signaling in the response using GLP-1 receptor, GLP-2 receptor and TGR5 knockout mice...
2021: Frontiers in Endocrinology
https://read.qxmd.com/read/33087457/pancreatic-sirtuin-3-deficiency-promotes-hepatic-steatosis-by-enhancing-5-hydroxytryptamine-synthesis-in-mice-with-diet-induced-obesity
#22
JOURNAL ARTICLE
Xing Ming, Arthur C K Chung, Dandan Mao, Huanyi Cao, Baoqi Fan, Willy K K Wong, Chin Chung Ho, Heung Man Lee, Kristina Schoonjans, Johan Auwerx, Guy A Rutter, Juliana C N Chan, Xiao Yu Tian, Alice P S Kong
Sirtuin 3 (SIRT3) is a protein deacetylase regulating β-cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of β-cell-specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs, are unknown. We found that glucose tolerance and glucose-stimulated insulin secretion were impaired in high-fat diet (HFD)-fed β-cell-selective Sirt3 knockout ( Sirt3 f/f;Cre/+ ) mice. In addition, Sirt3 f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3 f/f mice upon HFD feeding...
January 2021: Diabetes
https://read.qxmd.com/read/32986275/tgr5-cathepsin-e-signaling-regulates-macrophage-innate-immune-activation-in-liver-ischemia-and-reperfusion-injury
#23
JOURNAL ARTICLE
Haoming Zhou, Shun Zhou, Yong Shi, Qi Wang, Song Wei, Ping Wang, Feng Cheng, Johan Auwerx, Kristina Schoonjans, Ling Lu
The role and underlying mechanism of plasma membrane-bound G protein-coupled bile acid receptor (TGR5) in regulating macrophage innate immune activation during liver ischemia and reperfusion (IR) injury remains largely unclear. Here, we demonstrated that TGR5 depletion in myeloid cells aggravated liver injury with increased macrophage infiltration and enhanced inflammation in livers post IR. While TGR5 deficiency enhanced mobility and proinflammatory M1 polarization of macrophages, TGR5 agonist enhanced the anti-inflammatory effect of TGR5 both in vivo and in vitro...
September 28, 2020: American Journal of Transplantation
https://read.qxmd.com/read/32875282/transcriptomic-analysis-across-liver-diseases-reveals-disease-modulating-activation-of-constitutive-androstane-receptor-in-cholestasis
#24
JOURNAL ARTICLE
Bhoomika Mathur, Waqar Arif, Megan E Patton, Rahiman Faiyaz, Jian Liu, Jennifer Yeh, Sanjiv Harpavat, Kristina Schoonjans, Auinash Kalsotra, Antony M Wheatley, Sayeepriyadarshini Anakk
Background & Aims: Liver diseases are caused by many factors, such as genetics, nutrition, and viruses. Therefore, it is important to delineate transcriptomic changes that occur in various liver diseases. Methods: We performed high-throughput sequencing of mouse livers with diverse types of injuries, including cholestasis, diet-induced steatosis, and partial hepatectomy. Comparative analysis of liver transcriptome from mice and human samples of viral infections (HBV and HCV), alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH), and biliary atresia revealed distinct and overlapping gene profiles associated with liver diseases...
October 2020: JHEP reports: innovation in hepatology
https://read.qxmd.com/read/32790577/molecular-physiology-of-bile-acid-signaling-in-health-disease-and-aging
#25
REVIEW
Alessia Perino, Hadrien Demagny, Laura Velazquez-Villegas, Kristina Schoonjans
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling...
April 1, 2021: Physiological Reviews
https://read.qxmd.com/read/32708970/compound-18-improves-glucose-tolerance-in-a-hepatocyte-tgr5-dependent-manner-in-mice
#26
JOURNAL ARTICLE
Marlena M Holter, Margot K Chirikjian, Daniel A Briere, Adriano Maida, Kyle W Sloop, Kristina Schoonjans, Bethany P Cummings
The bile acid receptor, TGR5, is a key regulator of glucose homeostasis, but the mechanisms by which TGR5 signaling improves glucose regulation are incompletely defined. In particular, TGR5 has an increasingly appreciated role in liver physiology and pathobiology; however, whether TGR5 signaling within the liver contributes to its glucoregulatory effects is unknown. Therefore, we investigated the role of hepatocyte TGR5 signaling on glucose regulation using a hepatocyte-specific TGR5 knockout mouse model. Hepatocyte-specific Tgr5Hep+/+ and Tgr5Hep-/- mice were fed a high fat diet (HFD) for 7 weeks and then orally gavaged with three doses of a highly potent, TGR5-specific agonist, Compound 18 (10 mg/kg), or vehicle, over 72 h and underwent an oral glucose tolerance test (OGTT) after the last dose...
July 17, 2020: Nutrients
https://read.qxmd.com/read/32661285/maternal-glucose-homeostasis-is-impaired-in-mouse-models-of-gestational-cholestasis
#27
JOURNAL ARTICLE
Elena Bellafante, Saraid McIlvride, Vanya Nikolova, Hei Man Fan, Luiza Borges Manna, Jenny Chambers, Mavis Machirori, Anita Banerjee, Kevin Murphy, Marcus Martineau, Kristina Schoonjans, Hanns-Ulrich Marschall, Peter Jones, Catherine Williamson
Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance...
July 13, 2020: Scientific Reports
https://read.qxmd.com/read/32651372/mechano-modulatory-synthetic-niches-for-liver-organoid-derivation
#28
JOURNAL ARTICLE
Giovanni Sorrentino, Saba Rezakhani, Ece Yildiz, Sandro Nuciforo, Markus H Heim, Matthias P Lutolf, Kristina Schoonjans
The recent demonstration that primary cells from the liver can be expanded in vitro as organoids holds enormous promise for regenerative medicine and disease modelling. The use of three-dimensional (3D) cultures based on ill-defined and potentially immunogenic matrices, however, hampers the translation of liver organoid technology into real-life applications. We here use chemically defined hydrogels for the efficient derivation of both mouse and human hepatic organoids. Organoid growth is found to be highly stiffness-sensitive, a mechanism independent of acto-myosin contractility and requiring instead activation of the Src family of kinases (SFKs) and yes-associated protein 1 (YAP)...
July 10, 2020: Nature Communications
https://read.qxmd.com/read/32485177/bile-acids-signal-via-tgr5-to-activate-intestinal-stem-cells-and-epithelial-regeneration
#29
JOURNAL ARTICLE
Giovanni Sorrentino, Alessia Perino, Ece Yildiz, Gaby El Alam, Maroun Bou Sleiman, Antimo Gioiello, Roberto Pellicciari, Kristina Schoonjans
BACKGROUND & AIMS: Renewal and patterning of the intestinal epithelium is coordinated by intestinal stem cells (ISCs); dietary and metabolic factors provide signals to the niche that control ISC activity. Bile acids (BAs), metabolites in the gut, signal nutrient availability by activating the G protein-coupled bile acid receptor 1 (GPBAR1, also called TGR5). TGR5 is expressed in the intestinal epithelium, but it is not clear how its activation affects ISCs and regeneration of the intestinal epithelium...
September 2020: Gastroenterology
https://read.qxmd.com/read/32041793/l-cell-differentiation-is-induced-by-bile-acids-through-gpbar1-and-paracrine-glp-1-and-serotonin-signaling
#30
JOURNAL ARTICLE
Mari Lilith Lund, Giovanni Sorrentino, Kristoffer Lihme Egerod, Chantal Kroone, Brynjulf Mortensen, Filip Krag Knop, Frank Reimann, Fiona M Gribble, Daniel J Drucker, Eelco J P de Koning, Kristina Schoonjans, Fredrik Bäckhed, Thue W Schwartz, Natalia Petersen
Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein-coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1 L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo...
April 2020: Diabetes
https://read.qxmd.com/read/31754022/identifying-gene-function-and-module-connections-by-the-integration-of-multispecies-expression-compendia
#31
JOURNAL ARTICLE
Hao Li, Daria Rukina, Fabrice P A David, Terytty Yang Li, Chang-Myung Oh, Arwen W Gao, Elena Katsyuba, Maroun Bou Sleiman, Andrea Komljenovic, Qingyao Huang, Robert W Williams, Marc Robinson-Rechavi, Kristina Schoonjans, Stephan Morgenthaler, Johan Auwerx
The functions of many eukaryotic genes are still poorly understood. Here, we developed and validated a new method, termed GeneBridge, which is based on two linked approaches to impute gene function and bridge genes with biological processes. First, <u>G</u>ene-<u>M</u>odule <u>A</u>ssociation <u>D</u>etermination (G-MAD) allows the annotation of gene function. Second, <u>M</u>odule-<u>M</u>odule <u>A</u>ssociation <u>D</u>etermination (M-MAD) allows predicting connectivity among modules...
December 2019: Genome Research
https://read.qxmd.com/read/31752395/the-g-protein-coupled-bile-acid-receptor-tgr5-gpbar1-modulates-endothelin-1-signaling-in-liver
#32
JOURNAL ARTICLE
Caroline Klindt, Maria Reich, Birte Hellwig, Jan Stindt, Jörg Rahnenführer, Jan G Hengstler, Karl Köhrer, Kristina Schoonjans, Dieter Häussinger, Verena Keitel
TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs), and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice...
November 19, 2019: Cells
https://read.qxmd.com/read/31461657/the-ovulatory-signal-precipitates-lrh-1-transcriptional-switching-mediated-by-differential-chromatin-accessibility
#33
JOURNAL ARTICLE
Stéphanie Bianco, Anne-Marie Bellefleur, Élaine Beaulieu, Charles Joly Beauparlant, Kalyne Bertolin, Arnaud Droit, Kristina Schoonjans, Bruce D Murphy, Nicolas Gévry
In the ovary, follicular growth and maturation are complicated processes that involve a series of morphological and physiological changes in oocytes and somatic cells leading to ovulation and luteinization, essential processes for fertility. Given the complexity of ovulation, characterization of genome-wide regulatory elements is essential to understand the mechanisms governing the expression of specific genes in the rapidly differentiating follicle. We therefore employed a systems biology approach to determine global transcriptional mechanisms during the early stages of the ovulatory process...
August 27, 2019: Cell Reports
https://read.qxmd.com/read/31328159/the-orphan-nuclear-receptor-lrh-1-nr5a2-critically-regulates-t-cell-functions
#34
JOURNAL ARTICLE
Carina Seitz, Juan Huang, Anna-Lena Geiselhöringer, Pamela Galbani-Bianchi, Svenja Michalek, Truong San Phan, Cindy Reinhold, Lea Dietrich, Christian Schmidt, Nadia Corazza, Eugenia Delgado, Theresa Schnalzger, Kristina Schoonjans, Thomas Brunner
LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell-specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1-depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation...
July 2019: Science Advances
https://read.qxmd.com/read/31237863/ntcp-deficiency-in-mice-protects-against-obesity-and-hepatosteatosis
#35
JOURNAL ARTICLE
Joanne M Donkers, Sander Kooijman, Davor Slijepcevic, Roni F Kunst, Reinout Lp Roscam Abbing, Lizette Cjm Haazen, Dirk R de Waart, Johannes Hm Levels, Kristina Schoonjans, Patrick Cn Rensen, Ronald Pj Oude Elferink, Stan Fj Van de Graaf
Bile acids play a major role in the regulation of lipid and energy metabolism. Here we propose the hepatic bile acid uptake transporter Na+ taurocholate co-transporting polypeptide (NTCP) as a target to prolong postprandial bile acid elevations in plasma. Reducing hepatic clearance of bile acids from plasma by genetic deletion of NTCP moderately increased plasma bile acid levels, reduced diet-induced obesity, attenuated hepatic steatosis, and lowered plasma cholesterol levels. NTCP-G protein-coupled bile acid receptor (TGR5) double knockout mice were equally protected against diet-induced-obesity as NTCP single knockout mice...
June 25, 2019: JCI Insight
https://read.qxmd.com/read/31061415/a-new-class-of-protein-biomarkers-based-on-subcellular-distribution-application-to-a-mouse-liver-cancer-model
#36
JOURNAL ARTICLE
Tatjana Sajic, Rodolfo Ciuffa, Vera Lemos, Pan Xu, Valentina Leone, Chen Li, Evan G Williams, Georgios Makris, Amir Banaei-Esfahani, Mathias Heikenwalder, Kristina Schoonjans, Ruedi Aebersold
To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in association with other proteins to form modules localized in particular subcellular compartments in specialized cell types and tissues. Sub-cellular mislocalization of proteins has in fact been detected as a key feature in a variety of cancer cells. Here, we describe a strategy for tissue-biomarker detection based on a mitochondrial fold enrichment (mtFE) score, which is sensitive to protein abundance changes as well as changes in subcellular distribution between mitochondria and cytosol...
May 6, 2019: Scientific Reports
https://read.qxmd.com/read/30767682/bile-acids-drive-colonic-secretion-of-glucagon-like-peptide-1-and-peptide-yy-in-rodents
#37
JOURNAL ARTICLE
Charlotte Bayer Christiansen, Samuel Addison Jack Trammell, Nicolai Jacob Wewer Albrechtsen, Kristina Schoonjans, Reidar Albrechtsen, Matthew Paul Gillum, Rune Ehrenreich Kuhre, Jens Juul Holst
A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3...
May 1, 2019: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://read.qxmd.com/read/30642763/the-rna-binding-protein-pum2-impairs-mitochondrial-dynamics-and-mitophagy-during-aging
#38
JOURNAL ARTICLE
Davide D'Amico, Adrienne Mottis, Francesca Potenza, Vincenzo Sorrentino, Hao Li, Mario Romani, Vera Lemos, Kristina Schoonjans, Nicola Zamboni, Graham Knott, Bernard L Schneider, Johan Auwerx
Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (Mff), thereby impairing mitochondrial fission and mitophagy. This mechanism is conserved in C...
February 21, 2019: Molecular Cell
https://read.qxmd.com/read/30356218/de-novo-nad-synthesis-enhances-mitochondrial-function-and-improves-health
#39
JOURNAL ARTICLE
Elena Katsyuba, Adrienne Mottis, Marika Zietak, Francesca De Franco, Vera van der Velpen, Karim Gariani, Dongryeol Ryu, Lucia Cialabrini, Olli Matilainen, Paride Liscio, Nicola Giacchè, Nadine Stokar-Regenscheit, David Legouis, Sophie de Seigneux, Julijana Ivanisevic, Nadia Raffaelli, Kristina Schoonjans, Roberto Pellicciari, Johan Auwerx
Nicotinamide adenine dinucleotide (NAD+ ) is a co-substrate for several enzymes, including the sirtuin family of NAD+ -dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse...
November 2018: Nature
https://read.qxmd.com/read/29662071/lrh-1-agonism-favours-an-immune-islet-dialogue-which-protects-against-diabetes-mellitus
#40
JOURNAL ARTICLE
Nadia Cobo-Vuilleumier, Petra I Lorenzo, Noelia García Rodríguez, Irene de Gracia Herrera Gómez, Esther Fuente-Martin, Livia López-Noriega, José Manuel Mellado-Gil, Silvana-Yanina Romero-Zerbo, Mathurin Baquié, Christian Claude Lachaud, Katja Stifter, German Perdomo, Marco Bugliani, Vincenzo De Tata, Domenico Bosco, Geraldine Parnaud, David Pozo, Abdelkrim Hmadcha, Javier P Florido, Miguel G Toscano, Peter de Haan, Kristina Schoonjans, Luis Sánchez Palazón, Piero Marchetti, Reinhold Schirmbeck, Alejandro Martín-Montalvo, Paolo Meda, Bernat Soria, Francisco-Javier Bermúdez-Silva, Luc St-Onge, Benoit R Gauthier
Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis...
April 16, 2018: Nature Communications
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