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1
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Jamerson LE, Bradshaw PC. The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity. Antioxidants (Basel) 2024; 13:820. [PMID: 39061889 PMCID: PMC11273496 DOI: 10.3390/antiox13070820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that of NADPH-generating enzymes that fuel lipogenesis in white adipose tissue (WAT) through the induction of transcriptional regulators SREBP-1c and CHREBP. SREBP-1c knockout mice, unlike controls, did not show an extended lifespan on the DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) and the pentose phosphate pathway (PPP), while liver cytoplasmic NADPH is primarily synthesized by folate cycle enzymes provided one-carbon units through serine catabolism. During the daily fasting period of the DR diet, fatty acids are released from WAT and are transported to peripheral tissues, where they are used for beta-oxidation and for phospholipid and lipid droplet synthesis, where monounsaturated fatty acids (MUFAs) may activate Nrf1 and inhibit ferroptosis to promote longevity. Decreased WAT NADPH from PPP gene knockout stimulated the browning of WAT and protected from a high-fat diet, while high levels of NADPH-generating enzymes in WAT and macrophages are linked to obesity. But oscillations in WAT [NADPH]/[NADP+] from feeding and fasting cycles may play an important role in maintaining metabolic plasticity to drive longevity. Studies measuring the WAT malate/pyruvate as a proxy for the cytoplasmic [NADPH]/[NADP+], as well as studies using fluorescent biosensors expressed in the WAT of animal models to monitor the changes in cytoplasmic [NADPH]/[NADP+], are needed during ad libitum and DR diets to determine the changes that are associated with longevity.
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Affiliation(s)
| | - Patrick C. Bradshaw
- Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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2
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Di Martino E, Ambikan A, Ramsköld D, Umekawa T, Giatrellis S, Vacondio D, Romero AL, Galán MG, Sandberg R, Ådén U, Lauschke VM, Neogi U, Blomgren K, Kele J. Inflammatory, metabolic, and sex-dependent gene-regulatory dynamics of microglia and macrophages in neonatal hippocampus after hypoxia-ischemia. iScience 2024; 27:109346. [PMID: 38500830 PMCID: PMC10945260 DOI: 10.1016/j.isci.2024.109346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 01/02/2024] [Accepted: 02/22/2024] [Indexed: 03/20/2024] Open
Abstract
Neonatal hypoxia-ischemia (HI) is a major cause of perinatal death and long-term disabilities worldwide. Post-ischemic neuroinflammation plays a pivotal role in HI pathophysiology. In the present study, we investigated the temporal dynamics of microglia (CX3CR1GFP/+) and infiltrating macrophages (CCR2RFP/+) in the hippocampi of mice subjected to HI at postnatal day 9. Using inflammatory pathway and transcription factor (TF) analyses, we identified a distinct post-ischemic response in CCR2RFP/+ cells characterized by differential gene expression in sensome, homeostatic, matrisome, lipid metabolic, and inflammatory molecular signatures. Three days after injury, transcriptomic signatures of CX3CR1GFP/+ and CCR2RFP/+ cells isolated from hippocampi showed a partial convergence. Interestingly, microglia-specific genes in CX3CR1GFP/+ cells showed a sexual dimorphism, where expression returned to control levels in males but not in females during the experimental time frame. These results highlight the importance of further investigations on metabolic rewiring to pave the way for future interventions in asphyxiated neonates.
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Affiliation(s)
- Elena Di Martino
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden
| | - Anoop Ambikan
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Huddinge, Sweden
| | - Daniel Ramsköld
- Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Takashi Umekawa
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Sarantis Giatrellis
- Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Davide Vacondio
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden
| | | | - Marta Gómez Galán
- Department of Physiology and Pharmacology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Rickard Sandberg
- Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Ulrika Ådén
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden
- Neonatology, Karolinska University Hospital, Stockholm, Sweden
| | - Volker M. Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, 17165 Stockholm, Sweden
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany
- University of Tuebingen, 72074 Tuebingen, Germany
| | - Ujjwal Neogi
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Huddinge, Sweden
| | - Klas Blomgren
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden
- Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Julianna Kele
- Department of Physiology and Pharmacology, Karolinska Institutet, 17165 Stockholm, Sweden
- Team Neurovascular Biology and Health, Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Huddinge, Sweden
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3
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Zhu F, Ma J, Li W, Liu Q, Qin X, Qian Y, Wang C, Zhang Y, Li Y, Jiang D, Wang S, Xia P. The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome. Immunity 2023; 56:753-767.e8. [PMID: 37001519 DOI: 10.1016/j.immuni.2023.03.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/07/2022] [Accepted: 03/01/2023] [Indexed: 04/14/2023]
Abstract
Intracellular sensing of lipopolysaccharide (LPS) by murine caspase-11 or human caspase-4 initiates a protease cascade, termed the non-canonical inflammasome, that results in gasdermin D (GSDMD) processing and subsequent NLRP3 inflammasome activation. In an effort aimed at identifying additional sensors for intracellular LPS by biochemical screening, we identified the nuclear orphan receptor Nur77 as an LPS-binding protein in macrophage lysates. Nr4a1-/- macrophages exhibited impaired activation of the NLRP3 inflammasome, but not caspase-11, in response to LPS. Biochemical mapping revealed that Nur77 bound LPS directly through a domain in its C terminus. Yeast two-hybrid assays identified NLRP3 as a binding partner for Nur77. The association between Nur77 and NLRP3 required the presence of LPS and dsDNA. The source of dsDNA was the mitochondria, requiring the formation of gasdermin-D pores. In vivo, Nur77 deficiency ameliorated host response to endotoxins. Thus, Nur77 functions as an intracellular LPS sensor, binding mitochondrial DNA and LPS to activate the non-canonical NLRP3 inflammasome.
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Affiliation(s)
- Fangrui Zhu
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Juan Ma
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Weitao Li
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Qiannv Liu
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Xiwen Qin
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Yan Qian
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Chunlei Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Yan Zhang
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| | - Yi Li
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Dong Jiang
- Department of Sports Medicine, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, Beijing 100191, China
| | - Shuo Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Pengyan Xia
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China.
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4
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Garabuczi É, Tarban N, Fige É, Patsalos A, Halász L, Szendi-Szatmári T, Sarang Z, Király R, Szondy Z. Nur77 and PPARγ regulate transcription and polarization in distinct subsets of M2-like reparative macrophages during regenerative inflammation. Front Immunol 2023; 14:1139204. [PMID: 36936920 PMCID: PMC10020500 DOI: 10.3389/fimmu.2023.1139204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Macrophage polarization is a process whereby macrophages develop a specific phenotype and functional response to different pathophysiological stimuli and tissue environments. In general, two main macrophage phenotypes have been identified: inflammatory (M1) and alternatively activated (M2) macrophages characterized specifically by IL-1β and IL-10 production, respectively. In the cardiotoxin-induced skeletal muscle injury model bone marrow-derived macrophages (BMDMs) play the central role in regulating tissue repair. Bone marrow-derived monocytes arriving at the site of injury differentiate first to M1 BMDMs that clear cell debris and trigger proliferation and differentiation of the muscle stem cells, while during the process of efferocytosis they change their phenotype to M2 to drive resolution of inflammation and tissue repair. The M2 population is formed from at least three distinct subsets: antigen presenting, resolution-related and growth factor producing macrophages, the latest ones expressing the transcription factor PPARγ. Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77) transcription factor is expressed as an early response gene, and has been shown to suppress the expression of pro-inflammatory genes during efferocytosis. Here we demonstrate that (1) Nur77 null BMDMs are characterized by elevated expression of PPARγ resulting in enhanced efferocytosis capacity; (2) Nur77 and PPARγ regulate transcription in different subsets of M2 skeletal muscle macrophages during muscle repair; (3) the loss of Nur77 prolongs M1 polarization characterized by increased and prolonged production of IL-1β by the resolution-related macrophages normally expressing Nur77; whereas, in contrast, (4) it promotes M2 polarization detected via the increased number of IL-10 producing CD206+ macrophages generated from the PPARγ-expressing subset.
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Affiliation(s)
- Éva Garabuczi
- Department of Integrative Health Sciences, Institute of Health Sciences, Faculty of Health Sciences, University of Debrecen, Debrecen, Hungary
| | - Nastaran Tarban
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Éva Fige
- Doctoral School of Dental Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
| | - Andreas Patsalos
- Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
| | - László Halász
- Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
| | - Tímea Szendi-Szatmári
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsolt Sarang
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Róbert Király
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsuzsa Szondy
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Section of Dental Biochemistry, Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
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5
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Lockridge A, Hanover JA. A nexus of lipid and O-Glcnac metabolism in physiology and disease. Front Endocrinol (Lausanne) 2022; 13:943576. [PMID: 36111295 PMCID: PMC9468787 DOI: 10.3389/fendo.2022.943576] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Although traditionally considered a glucose metabolism-associated modification, the O-linked β-N-Acetylglucosamine (O-GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of O-GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental sensors. By direct protein-protein interactions and catalytic modification, O-GlcNAc cycling enzymes may provide both acute and long-term adaptation to stress and other environmental stimuli such as nutrient availability. Depending on the cell type, hyperlipidemia potentiates or depresses O-GlcNAc levels, sometimes biphasically, through a diversity of unique mechanisms that target UDP-GlcNAc synthesis and the availability, activity and substrate selectivity of the glycosylation enzymes, O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). At the same time, OGT activity in multiple tissues has been implicated in the homeostatic regulation of systemic lipid uptake, storage and release. Hyperlipidemic patterns of O-GlcNAcylation in these cells are consistent with both transient physiological adaptation and feedback uninhibited obesogenic and metabolic dysregulation. In this review, we summarize the numerous interconnections between lipid and O-GlcNAc metabolism. These links provide insights into how the O-GlcNAc regulatory system may contribute to lipid-associated diseases including obesity and metabolic syndrome.
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Affiliation(s)
- Amber Lockridge
- Laboratory of Cell and Molecular Biology, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - John A. Hanover
- Laboratory of Cell and Molecular Biology, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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6
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Kimura S, Tsuruma A, Kato E. Taste 2 Receptor Is Involved in Differentiation of 3T3-L1 Preadipocytes. Int J Mol Sci 2022; 23:ijms23158120. [PMID: 35897692 PMCID: PMC9331636 DOI: 10.3390/ijms23158120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
Expression of taste 2 receptor (T2R) genes, also known as bitter taste receptor genes, has been reported in a variety of tissues. The white adipose tissue of mice has been shown to express Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, but the function of T2Rs in adipocytes remains unclear. Here, we show that fasting and stimulation by bitter compounds both increased Tas2r expression in mouse white adipose tissue, and serum starvation and stimulation by bitter compounds both increased the expression of Tas2r genes in 3T3-L1 adipocytes, suggesting that T2Rs have functional roles in adipocytes. RNA sequencing analysis of 3T3-L1 adipocytes stimulated by epicatechin, the ligand of Tas2r126, suggested that this receptor may play a role in the differentiation of adipocytes. Overexpression of Tas2r126 in 3T3-L1 preadipocytes decreases fat accumulation after induction of differentiation and reduces the expression of adipogenic genes. Together, these results indicate that Tas2r126 may be involved in adipocyte differentiation.
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Affiliation(s)
- Shunsuke Kimura
- Graduate School of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan; (S.K.); (A.T.)
- Japan Society for the Promotion of Science (JSPS), Chiyoda-ku, Tokyo 102-0083, Japan
| | - Ai Tsuruma
- Graduate School of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan; (S.K.); (A.T.)
| | - Eisuke Kato
- Division of Fundamental AgriScience and Research, Research Faculty of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan
- Correspondence:
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7
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Xu Y, Tian J, Kang Q, Yuan H, Liu C, Li Z, Liu J, Li M. Knockout of Nur77 Leads to Amino Acid, Lipid, and Glucose Metabolism Disorders in Zebrafish. Front Endocrinol (Lausanne) 2022; 13:864631. [PMID: 35547009 PMCID: PMC9084189 DOI: 10.3389/fendo.2022.864631] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/14/2022] [Indexed: 12/25/2022] Open
Abstract
Orphan nuclear receptor Nur77 has been reported to be implicated in a diverse range of metabolic processes, including carbohydrate metabolism and lipid metabolism. However, the detailed mechanism of Nur77 in the regulation of metabolic pathway still needs to be further investigated. In this study, we created a global nur77 knockout zebrafish model by CRISPR/Cas9 technique, and then performed whole-organism RNA sequencing analysis in wildtype and nur77-deficient zebrafish to dissect the genetic changes in metabolic-related pathways. We found that many genes involved in amino acid, lipid, and carbohydrate metabolism changed by more than twofold. Furthermore, we revealed that nur77-/- mutant displayed increased total cholesterol (TC) and triglyceride (TG), alteration in total amino acids, as well as elevated glucose. We also demonstrated that the elevated glucose was not due to the change of glucose uptake but was likely caused by the disorder of glycolysis/gluconeogenesis and the impaired β-cell function, including downregulated insb expression, reduced β-cell mass, and suppressed insulin secretion. Importantly, we also verified that targeted expression of Nur77 in the β cells is sufficient to rescue the β-cell defects in global nur77-/- larvae zebrafish. These results provide new information about the global metabolic network that Nur77 signaling regulates, as well as the role of Nur77 in β-cell function.
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Affiliation(s)
- Yang Xu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Juanjuan Tian
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Qi Kang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Hang Yuan
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Chengdong Liu
- Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China
| | - Zhehui Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Jie Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- *Correspondence: Mingyu Li, ; Jie Liu,
| | - Mingyu Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- *Correspondence: Mingyu Li, ; Jie Liu,
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8
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Ibrahim M, Ayoub D, Wasselin T, Van Dorsselaer A, Le Maho Y, Raclot T, Bertile F. Alterations in rat adipose tissue transcriptome and proteome in response to prolonged fasting. Biol Chem 2021; 401:389-405. [PMID: 31398141 DOI: 10.1515/hsz-2019-0184] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 07/18/2019] [Indexed: 12/13/2022]
Abstract
Various pathophysiological situations of negative energy balance involve the intense depletion of the body's energy reserves. White adipose tissue is a central place to store energy and a major endocrine organ. As a model of choice to better understand how the white adipose tissue dynamically responds to changes in substrate availability, we used the prolonged fasting paradigm, which is characterized by successive periods of stimulated (phase 2) and then reduced (phase 3) lipid mobilization/utilization. Using omics analyses, we report a regulatory transcriptional program in rat epididymal (EPI) adipose tissue favoring lipolysis during phase 2 and repressing it during phase 3. Changes in gene expression levels of lipases, lipid droplet-associated factors, and the proteins involved in cAMP-dependent and cAMP-independent regulation of lipolysis are highlighted. The mRNA and circulating levels of adipose-secreted factors were consistent with the repression of insulin signaling during prolonged fasting. Other molecular responses are discussed, including the regulation of leptin and adiponectin levels, the specific changes reflecting an increased fibrinolysis and a possible protein catabolism-related energy saving mechanism in late fasting. Finally, some differences between internal and subcutaneous (SC) adipose tissues are also reported. These data provide a comprehensive molecular basis of adipose tissue responses when facing a major energetic challenge.
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Affiliation(s)
- Marianne Ibrahim
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Laboratoire de Spectrométrie de Masse Bio-Organique, 25 rue Becquerel, F-67087 Strasbourg, France
| | - Daniel Ayoub
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Laboratoire de Spectrométrie de Masse Bio-Organique, 25 rue Becquerel, F-67087 Strasbourg, France
| | - Thierry Wasselin
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Laboratoire de Spectrométrie de Masse Bio-Organique, 25 rue Becquerel, F-67087 Strasbourg, France
| | - Alain Van Dorsselaer
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Laboratoire de Spectrométrie de Masse Bio-Organique, 25 rue Becquerel, F-67087 Strasbourg, France
| | - Yvon Le Maho
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Département Ecologie, Physiologie, Ethologie, 23 rue Becquerel, F-67087 Strasbourg, France
| | - Thierry Raclot
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Département Ecologie, Physiologie, Ethologie, 23 rue Becquerel, F-67087 Strasbourg, France
| | - Fabrice Bertile
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.,Laboratoire de Spectrométrie de Masse Bio-Organique, 25 rue Becquerel, F-67087 Strasbourg, France
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9
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Ma S, Zhou B, Yang Q, Pan Y, Yang W, Freedland SJ, Ding LW, Freeman MR, Breunig JJ, Bhowmick NA, Pan J, Koeffler HP, Lin DC. A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma. Cancer Res 2021; 81:1216-1229. [PMID: 33402390 PMCID: PMC8026506 DOI: 10.1158/0008-5472.can-20-0652] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 08/21/2020] [Accepted: 12/17/2020] [Indexed: 11/16/2022]
Abstract
Although obesity is one of the strongest risk factors for esophageal adenocarcinoma, the molecular mechanisms underlying this association remain unclear. We recently identified four esophageal adenocarcinoma-specific master regulator transcription factors (MRTF) ELF3, KLF5, GATA6, and EHF. In this study, gene-set enrichment analysis of both esophageal adenocarcinoma patient samples and cell line models unbiasedly underscores fatty acid synthesis as the central pathway downstream of three MRTFs (ELF3, KLF5, GATA6). Further characterizations unexpectedly identified a transcriptional feedback loop between MRTF and fatty acid synthesis, which mutually activated each other through the nuclear receptor, PPARG. MRTFs cooperatively promoted PPARG transcription by directly regulating its promoter and a distal esophageal adenocarcinoma-specific enhancer, leading to PPARG overexpression in esophageal adenocarcinoma. PPARG was also elevated in Barrett's esophagus, a recognized precursor to esophageal adenocarcinoma, implying that PPARG might play a role in the intestinal metaplasia of esophageal squamous epithelium. Upregulation of PPARG increased de novo synthesis of fatty acids, phospholipids, and sphingolipids as revealed by mass spectrometry-based lipidomics. Moreover, ChIP-seq, 4C-seq, and a high-fat diet murine model together characterized a novel, noncanonical, and cancer-specific function of PPARG in esophageal adenocarcinoma. PPARG directly regulated the ELF3 super-enhancer, subsequently activating the transcription of other MRTFs through an interconnected regulatory circuitry. Together, elucidation of this novel transcriptional feedback loop of MRTF/PPARG/fatty acid synthesis advances our understanding of the mechanistic foundation for epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma. More importantly, this work identifies a potential avenue for prevention and early intervention of esophageal adenocarcinoma by blocking this feedback loop. SIGNIFICANCE: These findings elucidate a transcriptional feedback loop linking epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma, indicating that blocking this feedback loop could be a potential therapeutic strategy in high-risk individuals.
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Affiliation(s)
- Sai Ma
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Bo Zhou
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Qian Yang
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yunzhi Pan
- Department of Pharmacy, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China
| | - Wei Yang
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephen J Freedland
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, USA and the Durham VA Medical Center, Durham, North Carolina
| | - Ling-Wen Ding
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Michael R Freeman
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Joshua J Breunig
- Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Neil A Bhowmick
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jian Pan
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China.
| | - H Phillip Koeffler
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - De-Chen Lin
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
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10
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Farhadi S, Shodja Ghias J, Hasanpur K, Mohammadi SA, Ebrahimie E. Molecular mechanisms of fat deposition: IL-6 is a hub gene in fat lipolysis, comparing thin-tailed with fat-tailed sheep breeds. Arch Anim Breed 2021; 64:53-68. [PMID: 34084904 PMCID: PMC8130542 DOI: 10.5194/aab-64-53-2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/18/2020] [Indexed: 12/14/2022] Open
Abstract
Tail fat content affects meat quality and varies significantly among different breeds of sheep. Ghezel (fat-tailed) and Zel (thin-tailed) are two important Iranian local sheep breeds with different patterns of fat storage. The current study presents the transcriptome characterization of tail fat using RNA sequencing in order to get a better comprehension of the molecular mechanism of lipid storage in the two mentioned sheep breeds. Seven (Zel = 4 and Ghezel = 3) 7-month-old male lambs were used for this experiment. The results of sequencing were analyzed with bioinformatics methods, including differentially expressed genes (DEGs) identification, functional enrichment analysis, structural classification of proteins, protein-protein interaction (PPI) and network and module analyses. Some of the DEGs, such as LIPG, SAA1, SOCS3, HIF-1 α , and especially IL-6, had a close association with lipid metabolism. Furthermore, functional enrichment analysis revealed pathways associated with fat deposition, including "fatty acid metabolism", "fatty acid biosynthesis" and "HIF-1 signaling pathway". The structural classification of proteins showed that major down-regulated DEGs in the Zel (thin-tailed) breed were classified under transporter class and that most of them belonged to the solute carrier transporter (SLC) families. In addition, DEGs under the transcription factor class with an important role in lipolysis were up-regulated in the Zel (thin-tailed) breed. Also, network analysis revealed that IL-6 and JUNB were hub genes for up-regulated PPI networks, and HMGCS1, VPS35 and VPS26A were hub genes for down-regulated PPI networks. Among the up-regulated DEGs, the IL-6 gene seems to play an important role in lipolysis of tail fat in thin-tailed sheep breeds via various pathways such as tumor necrosis factor (TNF) signaling and mitogen-activated protein kinase (MAPK) signaling pathways. Due to the probable role of the IL-6 gene in fat lipolysis and also due to the strong interaction of IL-6 with the other up-regulated DEGs, it seems that IL-6 accelerates the degradation of lipids in tail fat cells.
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Affiliation(s)
- Sana Farhadi
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | - Jalil Shodja Ghias
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | - Karim Hasanpur
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | | | - Esmaeil Ebrahimie
- School of Animal and Veterinary Sciences, The University of Adelaide, South Australia 5371, Australia
- School of BioSciences, The University of Melbourne, Melbourne, Australia
- Genomics Research Platform, School of Life Sciences, La Trobe University, Melbourne, Victoria 3086, Australia
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11
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Zhang C, Zhang B, Zhang X, Sun G, Sun X. Targeting Orphan Nuclear Receptors NR4As for Energy Homeostasis and Diabetes. Front Pharmacol 2020; 11:587457. [PMID: 33328994 PMCID: PMC7728612 DOI: 10.3389/fphar.2020.587457] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022] Open
Abstract
Orphan nuclear receptors are important members of the nuclear receptor family and may regulate cell proliferation, metabolism, differentiation, and apoptosis. NR4As, a subfamily of orphan nuclear receptors, have been reported to play key roles in carbohydrate and lipid metabolism and energy homeostasis. Popularity of obesity has resulted in a series of metabolic diseases such as diabetes and its complications. While imbalance of energy intake and expenditure is the main cause of obesity, the concrete mechanism of obesity has not been fully understood. It has been reported that NR4As have significant regulatory effects on energy homeostasis and diabetes and are expected to become new targets for discovering drugs for metabolic syndrome. A number of studies have demonstrated that abnormalities in metabolism induced by altered levels of NR4As may contribute to numerous diseases, such as chronic inflammation, tumorigenesis, diabetes and its complications, atherosclerosis, and other cardiovascular diseases. However, systematic reviews focusing on the roles of NR4As in mediating energy homeostasis and diabetes remain limited. Therefore, this article reviews the structure and regulation of NR4As and their critical function in energy homeostasis and diabetes, as well as small molecules that may regulate NR4As. Our work is aimed at providing valuable support for the research and development of drugs targeting NR4As for the treatment of obesity and related metabolic diseases.
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Affiliation(s)
- Chenyang Zhang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences, Beijing, China
| | - Bin Zhang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuelian Zhang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences, Beijing, China
| | - Guibo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaobo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences, Beijing, China
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12
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Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression. Proc Natl Acad Sci U S A 2020; 117:27412-27422. [PMID: 33087562 DOI: 10.1073/pnas.2002997117] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.
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13
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Lee K, Moon S, Park MJ, Koh IU, Choi NH, Yu HY, Kim YJ, Kong J, Kang HG, Kim SC, Kim BJ. Integrated Analysis of Tissue-Specific Promoter Methylation and Gene Expression Profile in Complex Diseases. Int J Mol Sci 2020; 21:E5056. [PMID: 32709145 PMCID: PMC7404266 DOI: 10.3390/ijms21145056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
This study investigated whether the promoter region of DNA methylation positively or negatively regulates tissue-specific genes (TSGs) and if it correlates with disease pathophysiology. We assessed tissue specificity metrics in five human tissues, using sequencing-based approaches, including 52 whole genome bisulfite sequencing (WGBS), 52 RNA-seq, and 144 chromatin immunoprecipitation sequencing (ChIP-seq) data. A correlation analysis was performed between the gene expression and DNA methylation levels of the TSG promoter region. The TSG enrichment analyses were conducted in the gene-disease association network (DisGeNET). The epigenomic association analyses of CpGs in enriched TSG promoters were performed using 1986 Infinium MethylationEPIC array data. A correlation analysis showed significant associations between the promoter methylation and 449 TSGs' expression. A disease enrichment analysis showed that diabetes- and obesity-related diseases were high-ranked. In an epigenomic association analysis based on obesity, 62 CpGs showed statistical significance. Among them, three obesity-related CpGs were newly identified and replicated with statistical significance in independent data. In particular, a CpG (cg17075888 of PDK4), considered as potential therapeutic targets, were associated with complex diseases, including obesity and type 2 diabetes. The methylation changes in a substantial number of the TSG promoters showed a significant association with metabolic diseases. Collectively, our findings provided strong evidence of the relationship between tissue-specific patterns of epigenetic changes and metabolic diseases.
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Affiliation(s)
- Kibaick Lee
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Sanghoon Moon
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Mi-Jin Park
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - In-Uk Koh
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Nak-Hyeon Choi
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Ho-Yeong Yu
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Young Jin Kim
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Jinhwa Kong
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Song Cheol Kim
- Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Bong-Jo Kim
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea; (K.L.); (S.M.); (M.-J.P.); (I.-U.K.); (N.-H.C.); (H.-Y.Y.); (Y.J.K.); (J.K.)
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14
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Ma L, Zhang M, Jin Y, Erdenee S, Hu L, Chen H, Cai Y, Lan X. Comparative Transcriptome Profiling of mRNA and lncRNA Related to Tail Adipose Tissues of Sheep. Front Genet 2018; 9:365. [PMID: 30250481 PMCID: PMC6139350 DOI: 10.3389/fgene.2018.00365] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 08/21/2018] [Indexed: 01/05/2023] Open
Abstract
The Lanzhou Fat-Tail sheep (LFTS, long fat-tailed sheep) is an endangered sheep breed in China with a fat tail compared to the traditional local varieties, Small Tail Han sheep (STHS, thin-tailed sheep) with a small tail, and Tibetan sheep (TS, short thin-tailed sheep) with a little tail. However, little is known regarding how tail fat deposition is regulated by long noncoding RNA (lncRNA). To evaluate the lncRNA and mRNA associated with tail fat deposition and development among these breeds, high-throughput RNA sequencing of three individuals each of LFTS, STHS, and TS were performed and analyzed in this study. RNA sequencing data from these three groups revealed 10 differentially expressed genes (DEGs) and 37 differentially expressed lncRNAs between the LFTS and STHS groups, 390 DEGs and 59 differentially expressed lncRNAs between the LFTS and TS groups, and 80 DEGs and 16 differentially expressed lncRNAs between the STHS and TS groups (p-value < 0.05 and fold change ≥ 2), respectively. Gene Ontology and pathway analysis of DEGs and target genes of differentially expressed lncRNAs revealed enrichment in fatty acid metabolism and fatty acid elongation-related pathways that contribute to fat deposition. Subsequently, the expression of 14 DEGs and 6 differentially expressed lncRNAs was validated by quantitative real-time PCR. Finally, two co-expression networks of differentially expressed mRNA and lncRNAs were constructed. The results suggested that some differentially expressed lncRNAs (TCONS_00372767, TCONS_00171926, TCONS_00054953, and TCONS_00373007) may play crucial roles as core lncRNAs in tail fat deposition processes. In summary, the present study extends the sheep tail fat lncRNA database and these differentially expressed mRNA and lncRNAs may provide novel candidate regulators for future genetic and molecular studies on tail fat deposition of sheep.
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Affiliation(s)
- Lin Ma
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Meng Zhang
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yunyun Jin
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Sarantsetseg Erdenee
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Linyong Hu
- Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, China
| | - Hong Chen
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yong Cai
- Science Experimental Center, Northwest University for Nationalities, Lanzhou, China.,College of Life Science and Engineering, Northwest University for Nationalities, Lanzhou, China
| | - Xianyong Lan
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
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15
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Zhao N, Li X, Feng Y, Han J, Feng Z, Li X, Wen Y. The Nuclear Orphan Receptor Nur77 Alleviates Palmitate-induced Fat Accumulation by Down-regulating G0S2 in HepG2 Cells. Sci Rep 2018; 8:4809. [PMID: 29556076 PMCID: PMC5859288 DOI: 10.1038/s41598-018-23141-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 03/07/2018] [Indexed: 12/11/2022] Open
Abstract
Excessive triglyceride accumulation in hepatocytes is the hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). Elevated levels of the saturated free fatty acid palmitate in obesity are a major contributor to excessive hepatic lipid accumulation. The nuclear orphan receptor Nur77 is a transcriptional regulator and a lipotoxicity sensor. Using human HepG2 hepatoma cells, this study aimed to investigate the functional role of Nur77 in palmitate-induced hepatic steatosis. The results revealed that palmitate significantly induced lipid accumulation and suppressed lipolysis in hepatocytes. In addition, palmitate significantly suppressed Nur77 expression and stimulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes. Nur77 overexpression significantly reduced palmitate-induced expression of PPARγ and its target genes. Moreover, Nur77 overexpression attenuated lipid accumulation and augmented lipolysis in palmitate-treated hepatocytes. Importantly, G0S2 knockdown significantly attenuated lipid accumulation and augmented lipolysis in palmitate-treated hepatocytes, whereas G0S2 knockdown had no effect on the palmitate-induced expression of Nur77, PPARγ, or PPARγ target genes. In summary, palmitate suppresses Nur77 expression in HepG2 cells, and Nur77 overexpression alleviates palmitate-induced hepatic fat accumulation by down-regulating G0S2. These results display a novel molecular mechanism linking Nur77-regulated G0S2 expression to palmitate-induced hepatic steatosis.
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Affiliation(s)
- Naiqian Zhao
- Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China.
| | - Xiaoyan Li
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
| | - Ying Feng
- Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China
| | - Jinxiang Han
- Department of Gerontology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China
| | - Ziling Feng
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
| | - Xifeng Li
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
| | - Yanfang Wen
- Department of Infectious Diseases, First People's Hospital of Jinzhong, 85 Shuncheng Street, Jinzhong, 030600, Shanxi, China
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16
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Zhang L, Wang Q, Liu W, Liu F, Ji A, Li Y. The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases. J Diabetes Res 2018; 2018:9363461. [PMID: 30013988 PMCID: PMC6022324 DOI: 10.1155/2018/9363461] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 03/12/2018] [Accepted: 03/20/2018] [Indexed: 12/19/2022] Open
Abstract
Orphan nuclear receptor 4A1 (NR4A1) is a transcriptional factor of the nuclear orphan receptor (NR4A) superfamily that has sparked interest across different research fields in recent years. Several studies have demonstrated that ligand-independent NR4A1 is an immediate-early response gene and the protein product is rapidly induced by a variety of stimuli. Hyperfunction or dysfunction of NR4A1 is implicated in various metabolic processes, including carbohydrate metabolism, lipid metabolism, and energy balance, in major metabolic tissues, such as liver, skeletal muscle, pancreatic tissues, and adipose tissues. No endogenous ligands for NR4A1 have been identified, but numerous compounds that bind and activate or inactivate nuclear NR4A1 or induce cytoplasmic localization of NR4A1 have been identified. This review summarizes recent advances in our understanding of the molecular biology and physiological functions of NR4A1. And we focus on the physiological functions of NR4A1 receptor to the development of the metabolic diseases, with a special focus on the impact on carbohydrate and lipid metabolism in skeletal muscle, liver, adipose tissue, and islet.
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Affiliation(s)
- Lei Zhang
- Henan University School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
| | - Qun Wang
- Henan University School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
| | - Wen Liu
- Henan University School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
| | - Fangyan Liu
- Henan University School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
| | - Ailing Ji
- Henan University School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
| | - Yanzhang Li
- Henan University School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
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17
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Zhao NQ, Li XY, Wang L, Feng ZL, Li XF, Wen YF, Han JX. Palmitate induces fat accumulation by activating C/EBPβ-mediated G0S2 expression in HepG2 cells. World J Gastroenterol 2017; 23:7705-7715. [PMID: 29209111 PMCID: PMC5703930 DOI: 10.3748/wjg.v23.i43.7705] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 09/27/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the role of G0/G1 switch gene 2 (G0S2) and its transcriptional regulation in palmitate-induced hepatic lipid accumulation.
METHODS HepG2 cells were treated with palmitate, or palmitate in combination with CCAAT/enhancer binding protein (C/EBP)β siRNA or G0S2 siRNA. The mRNA expression of C/EBPβ, peroxisome proliferator-activated receptor (PPAR)γ and PPARγ target genes (G0S2, GPR81, GPR109A and Adipoq) was examined by qPCR. The protein expression of C/EBPβ, PPARγ, and G0S2 was determined by Western blotting. Lipid accumulation was detected with Oil Red O staining and quantified by absorbance value of the extracted Oil Red O dye. Lipolysis was evaluated by measuring the amount of glycerol released into the medium.
RESULTS Palmitate caused a dose-dependent increase in lipid accumulation and a dose-dependent decrease in lipolysis in HepG2 cells. In addition, palmitate increased the mRNA expression of C/EBPβ, PPARγ, and PPARγ target genes (G0S2, GPR81, GPR109A, and Adipoq) and the protein expression of C/EBPβ, PPARγ, and G0S2 in a dose-dependent manner. Knockdown of C/EBPβ decreased palmitate-induced PPARγ and its target genes (G0S2, GPR81, GPR109A, and Adipoq) mRNA expression and palmitate-induced PPARγ and G0S2 protein expression in HepG2 cells. Knockdown of C/EBPβ also attenuated lipid accumulation and augmented lipolysis in palmitate-treated HepG2 cells. G0S2 knockdown attenuated lipid accumulation and augmented lipolysis, while G0S2 knockdown had no effects on the mRNA expression of C/EBPβ, PPARγ, and PPARγ target genes (GPR81, GPR109A and Adipoq) in palmitate-treated HepG2 cells.
CONCLUSION Palmitate can induce lipid accumulation in HepG2 cells by activating C/EBPβ-mediated G0S2 expression.
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Affiliation(s)
- Nai-Qian Zhao
- Department of Gerontology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xiao-Yan Li
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Li Wang
- Department of Gerontology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Zi-Ling Feng
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Xi-Fen Li
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Yan-Fang Wen
- Department of Infectious Diseases, the First People’s Hospital of Jinzhong, Jinzhong 030600, Shanxi Province, China
| | - Jin-Xiang Han
- Department of Gerontology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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18
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Comparative transcriptome analysis reveals potentially novel roles of Homeobox genes in adipose deposition in fat-tailed sheep. Sci Rep 2017; 7:14491. [PMID: 29101335 PMCID: PMC5670210 DOI: 10.1038/s41598-017-14967-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 10/18/2017] [Indexed: 12/12/2022] Open
Abstract
Adipose tissues are phenotypically, metabolically and functionally heterogeneous based on the sites of their deposition. Undesirable fat deposits in the body are often detrimental to animal and human health. To unravel the potential underlying mechanisms governing accumulation of adipose tissues in various regions of the body, i.e., subcutaneous (SAT), visceral (VAT) and tail (TAT), we profiled transcriptomes from Tan sheep, a Chinese indigenous breed with notable fat tail using RNA-seq. Upon comparison, we identified a total of 1,058 differentially expressed genes (DEGs) between the three adipose types (218, 324, and 795 in SAT/VAT, SAT/TAT, and VAT/TAT, respectively), from which several known key players were identified that are involved in lipid metabolic process, Wnt signals, Vitamin A metabolism, and transcriptional regulation of adipocyte differentiation. We also found that many elevated genes in VAT were notably enriched for key biological processes such as cytokine secretion, signaling molecule interaction and immune systems. Several developmental genes including HOXC11, HOXC12 and HOXC13, and adipose-expressed genes in the tail region, such as HOTAIR_2, HOTAIR_3 and SP9 were specially highlighted, indicating their strong associations with tail fat development in fat-tailed sheep. Our results provide new insight into exploring the specific fat deposition in tail, also contribute to the understanding of differences between adipose depots.
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Stojkov-Mimic NJ, Bjelic MM, Radovic SM, Mihajlovic AI, Sokanovic SJ, Baburski AZ, Janjic MM, Kostic TS, Andric SA. Intratesticular alpha1-adrenergic receptors mediate stress-disturbed transcription of steroidogenic stimulator NUR77 as well as steroidogenic repressors DAX1 and ARR19 in Leydig cells of adult rats. Mol Cell Endocrinol 2015; 412:309-19. [PMID: 26003139 DOI: 10.1016/j.mce.2015.05.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 05/16/2015] [Accepted: 05/17/2015] [Indexed: 11/21/2022]
Abstract
The aim of the present study was to define the role of testicular α1-adrenergic receptors (α1-ADRs) in stress-triggered adaptation of testosterone-producing Leydig cells of adult rats. Results showed that in vivo blockade of testicular α1-ADRs prevented partial recovery of circulating androgen levels registered after 10× repeated immobilization stress (10 × IMO). Moreover, α1-ADR-blockade diminished 10 × IMO-triggered recovery of Leydig cell androgen production, and abolished mitochondrial membrane potential recovery. In the same cells, 10 × IMO-induced increase in Star transcript was abolished, Lhcgr transcript decreased, while transcription of other steroidogenic proteins was not changed. α1-ADR-blockade recovered stress-induced decrease of Nur77, one of the main steroidogenic stimulator, while significantly reduced 10 × IMO-increased in the transcription of the main steroidogenic repressors, Arr19 and Dax1. In vitro experiments revealed an adrenaline-induced α1-ADR-mediated decrease in Nur77 transcription in Leydig cells. Adrenaline-induced increase of repressor Dax1 also involves ADRs in Leydig cells. Accordingly, α1-ADRs participate in some of the stress-triggered effects on the steroidogenic machinery of Leydig cells.
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Affiliation(s)
- Natasa J Stojkov-Mimic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Maja M Bjelic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Sava M Radovic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Aleksandar I Mihajlovic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Srdjan J Sokanovic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Aleksandar Z Baburski
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Marija M Janjic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Tatjana S Kostic
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
| | - Silvana A Andric
- Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
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Capone F, Guerriero E, Colonna G, Maio P, Mangia A, Marfella R, Paolisso G, Izzo F, Potenza N, Tomeo L, Castello G, Costantini S. The Cytokinome Profile in Patients with Hepatocellular Carcinoma and Type 2 Diabetes. PLoS One 2015; 10:e0134594. [PMID: 26226632 PMCID: PMC4520685 DOI: 10.1371/journal.pone.0134594] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 07/11/2015] [Indexed: 12/13/2022] Open
Abstract
Understanding the dynamics of the complex interaction network of cytokines, defined as ‘‘cytokinome’’, can be useful to follow progression and evolution of hepatocellular carcinoma (HCC) from its early stages as well as to define therapeutic strategies. Recently we have evaluated the cytokinome profile in patients with type 2 diabetes (T2D) and/or chronic hepatitis C (CHC) infection and/or cirrhosis suggesting specific markers for the different stages of the diseases. Since T2D has been identified as one of the contributory cause of HCC, in this paper we examined the serum levels of cytokines, growth factors, chemokines, as well as of other cancer and diabetes biomarkers in a discovery cohort of patients with T2D, chronic hepatitis C (CHC) and/or CHC-related HCC comparing them with a healthy control group to define a profile of proteins able to characterize these patients, and to recognize the association between diabetes and HCC. The results have evidenced that the serum levels of some proteins are significantly and differently up-regulated in all the patients but they increased still more when HCC develops on the background of T2D. Our results were verified also using a separate validation cohort. Furthermore, significant correlations between clinical and laboratory data characterizing the various stages of this complex disease, have been found. In overall, our results highlighted that a large and simple omics approach, such as that of the cytokinome analysis, supplemented by common biochemical and clinical data, can give a complete picture able to improve the prognosis of the various stages of the disease progression. We have also demonstrated by means of interactomic analysis that our experimental results correlate positively with the general metabolic picture that is emerging in the literature for this complex multifactorial disease.
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Affiliation(s)
- Francesca Capone
- CROM, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy
| | - Eliana Guerriero
- CROM, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy
| | - Giovanni Colonna
- Center of Medical Informatics-SIM/AOU-Second University of Naples, Naples, Italy
| | - Patrizia Maio
- Unita`Operativa Malattie Infettive, Azienda Ospedaliera di Rilievo Nazionale ''San Giuseppe Moscati", Avellino, Italy
| | - Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Raffaele Marfella
- Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy
| | - Giuseppe Paolisso
- Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy
| | - Francesco Izzo
- Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Caserta, Italy
| | | | - Giuseppe Castello
- CROM, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy
| | - Susan Costantini
- CROM, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy
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Pérez-Sieira S, López M, Nogueiras R, Tovar S. Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency. Sci Rep 2014; 4:4264. [PMID: 24584059 PMCID: PMC3939456 DOI: 10.1038/srep04264] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 02/14/2014] [Indexed: 01/11/2023] Open
Abstract
The NR4A is a subfamily of the orphan nuclear receptors (NR) superfamily constituted by three well characterized members: Nur77 (NR4A1), Nurr1 (NR4A2) and Nor 1 (NR4A3). They are implicated in numerous biological processes as DNA repair, arteriosclerosis, cell apoptosis, carcinogenesis and metabolism. Several studies have demonstrated the role of this subfamily on glucose metabolism, insulin sensitivity and energy balance. These studies have focused mainly in liver and skeletal muscle. However, its potential role in white adipose tissue (WAT), one of the most important tissues involved in the regulation of energy homeostasis, is not well-studied. The aim of this work was to elucidate the regulation of NR4A in WAT under different physiological and pathophysiological settings involved in energy balance such as fasting, postnatal development, gender, hormonal deficiency and pregnancy. We compared NR4A mRNA expression of Nur77, Nurr1 and Nor 1 and found a clear regulation by nutritional status, since the expression of the 3 isoforms is increased after fasting in a leptin-independent manner and sex steroid hormones also modulate NR4A expression in males and females. Our findings indicate that NR4A are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status.
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Affiliation(s)
- S Pérez-Sieira
- 1] Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - M López
- 1] Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - R Nogueiras
- 1] Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - S Tovar
- 1] Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
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Stojkov NJ, Janjic MM, Baburski AZ, Mihajlovic AI, Drljaca DM, Sokanovic SJ, Bjelic MM, Kostic TS, Andric SA. Sustained in vivo blockade of α₁-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells. Am J Physiol Endocrinol Metab 2013; 305:E194-204. [PMID: 23695211 DOI: 10.1152/ajpendo.00100.2013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
This study was designed to systematically analyze and evaluate the effects of in vivo blockade of α₁-adrenergic receptors (α₁-ADRs) on the stress-induced disturbance of steroidogenic machinery in Leydig cells. Parameters followed 1) steroidogenic enzymes/proteins, transcription factors, and cAMP/testosterone production; 2) the main hallmarks of stress (epinephrine, glucocorticoids); and 3) transcription profiles of ADRs and oxidases with high affinity to inactivate glucocorticoids. Results showed that sustained blockade of α₁-ADRs prevented stress-induced 1) decrease of the transcripts/proteins for main steroidogenic CYPs (CYP11A1, CYP17A1); 2) decrease of Scarb1 and Hsd3b1 transcripts; 3) decrease of transcript for Nur77, one of the main activator of the steroidogenic expression; and 4) increase of Dax1 and Arr19, the main steroidogenic repressors in Leydig cells. In the same cells, the expression of steroidogenic stimulatory factor Creb1, StAR, and androgen receptor increased. In this signaling scenario, stress-induced stimulation of Adra1a/Adra1b/Adrbk1 and Hsd11b2 (the unidirectional oxidase with high affinity to inactivate glucocorticoids) was not changed. Blockade additionally stimulated stress-increased transcription of the most abundantly expressed ADRs Adra1d/Adrb1/Adrb2 in Leydig cells. In the same cells, stress-decreased testosterone production, the main marker of Leydig cells functionality, was completely prevented, while reduction of cAMP, the main regulator of androgenesis, was partially prevented. Accordingly, the presented data provide a new molecular/transcriptional base for "fight/adaptation" of steroidogenic cells and new molecular insights into the role of α₁-ADRs in stress-impaired Leydig cell steroidogenesis. The results are important in term of wide use of α₁-ADR selective antagonists, alone/in combination, to treat high blood pressure, nightmares associated with posttraumatic stress disorder, and disrupted sexual health.
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Affiliation(s)
- Natasa J Stojkov
- Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia
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