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Aboy-Pardal MCM, Guadamillas MC, Guerrero CR, Català-Montoro M, Toledano-Donado M, Terrés-Domínguez S, Pavón DM, Jiménez-Jiménez V, Jimenez-Carretero D, Zamai M, Folgueira C, Cerezo A, Lolo FN, Nogueiras R, Sabio G, Sánchez-Álvarez M, Echarri A, Garcia R, Del Pozo MA. Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability. Nat Commun 2024; 15:10102. [PMID: 39609408 PMCID: PMC11605069 DOI: 10.1038/s41467-024-54224-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 11/05/2024] [Indexed: 11/30/2024] Open
Abstract
Adipocytes expand massively to accommodate excess energy stores and protect the organism from lipotoxicity. Adipose tissue expandability is at the center of disorders such as obesity and lipodystrophy; however, little is known about the relevance of adipocyte biomechanics on the etiology of these conditions. Here, we show in male mice in vivo that the adipocyte plasma membrane undergoes caveolar domain reorganization upon lipid droplet expansion. As the lipid droplet grows, caveolae disassemble to release their membrane reservoir and increase cell surface area, and transfer specific caveolar components to the LD surface. Adipose tissue null for caveolae is stiffer, shows compromised deformability, and is prone to rupture under mechanical compression. Mechanistically, phosphoacceptor Cav1 Tyr14 is required for caveolae disassembly: adipocytes bearing a Tyr14Phe mutation at this residue are stiffer and smaller, leading to decreased adiposity in vivo; exhibit deficient transfer of Cav1 and EHD2 to the LD surface, and show distinct Cav1 molecular dynamics and tension adaptation. These results indicate that Cav1 phosphoregulation modulates caveolar dynamics as a relevant component of the homeostatic mechanoadaptation of the differentiated adipocyte.
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Affiliation(s)
- María C M Aboy-Pardal
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Marta C Guadamillas
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Science and Agroforestal Technology and Genetics, Faculty of Biochemistry and Environmental Sciences, University of Castilla-La Mancha, Toledo, Spain
| | - Carlos R Guerrero
- ForceTool group, Instituto de Ciencia de Materiales de Madrid (ICMM), CSIC, Madrid, Spain
| | - Mauro Català-Montoro
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Mónica Toledano-Donado
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Sara Terrés-Domínguez
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Dácil M Pavón
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Allergy Therapeutics, Avenida Punto Es, 12, 28805 Alcalá de Henares, Madrid, Spain
| | - Víctor Jiménez-Jiménez
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Health Science, Universidad Católica Santa Teresa de Jesús de Ávila, Ávila, Spain
| | - Daniel Jimenez-Carretero
- Cellomics Unit, Cell and Developmental Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Moreno Zamai
- Microscopy and Dynamic Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Cintia Folgueira
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas CIMUS, Santiago de Compostela, Spain
- Stress kinases in Diabetes, Cancer and Cardiovascular Disease lab. Cardiovascular risk factors & brain function program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Ana Cerezo
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Molecular Pharmacology, Lilly Research Laboratories, Alcobendas, Spain
| | - Fidel-Nicolás Lolo
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Rubén Nogueiras
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas CIMUS, Santiago de Compostela, Spain
| | - Guadalupe Sabio
- Stress kinases in Diabetes, Cancer and Cardiovascular Disease lab. Cardiovascular risk factors & brain function program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Miguel Sánchez-Álvarez
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Cell Compartmentalization, Homeostasis and Inflammation lab, Department of Metabolic and Inflammatory Diseases. Instituto de Investigaciones Biomédicas "Sols-Morreale"-CSIC, Madrid, Spain
| | - Asier Echarri
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Mechanobiology of Organelles lab. Department of Cellular and Molecular Biology. Centro de Investigaciones Biológicas Margarita Salas - CSIC, Madrid, Spain
| | - Ricardo Garcia
- ForceTool group, Instituto de Ciencia de Materiales de Madrid (ICMM), CSIC, Madrid, Spain
| | - Miguel A Del Pozo
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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Krüger P, Hartinger R, Djabali K. Navigating Lipodystrophy: Insights from Laminopathies and Beyond. Int J Mol Sci 2024; 25:8020. [PMID: 39125589 PMCID: PMC11311807 DOI: 10.3390/ijms25158020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/06/2024] [Accepted: 07/16/2024] [Indexed: 08/12/2024] Open
Abstract
Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.
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Affiliation(s)
| | | | - Karima Djabali
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany; (P.K.); (R.H.)
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Huang M, Wang X, Chen Y, Pessoa MT, Terrell KC, Zhang J, Tian J, Xie Z, Pierre SV, Cai L. Role of Na/K-ATPase α1 caveolin-binding motif in adipogenesis. Am J Physiol Cell Physiol 2024; 327:C48-C64. [PMID: 38708522 PMCID: PMC11371328 DOI: 10.1152/ajpcell.00168.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/07/2024]
Abstract
Deficiencies in mice and in humans have brought to the fore the importance of the caveolar network in key aspects of adipocyte biology. The conserved N-terminal caveolin-binding motif (CBM) of the ubiquitous Na/K-ATPase (NKA) α1 isoform, which allows NKA/caveolin-1 (Cav1) interaction, influences NKA signaling and caveolar distribution. It has been shown to be critical for animal development and ontogenesis, as well as lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs). However, its role in postnatal adipogenesis has not been fully examined. Using a genetic approach to alter CBM in hiPSC-derived adipocytes (iAdi-mCBM) and in mice (mCBM), we investigated the regulatory function of NKA CBM signaling in adipogenesis. Seahorse XF cell metabolism analyses revealed impaired glycolysis and decreased ATP synthesis-coupled respiration in iAdi-mCBM. These metabolic dysfunctions were accompanied by evidence of extensive remodeling of the extracellular matrix (ECM), including increased collagen staining, overexpression of ECM marker genes, and heightened TGF-β signaling uncovered by RNAseq analysis. Rescue of mCBM by lentiviral delivery of WT NKA α1 or treatment of mCBM hiPSCs with the TGF-β inhibitor SB431542 normalized ECM, suggesting that NKA CBM signaling integrity is required for adequate control of TGF-β signaling and ECM stiffness during adipogenesis. The physiological impact was revealed in mCBM male mice with reduced fat mass accompanied by histological and transcriptional evidence of elevated adipose fibrosis and decreased adipocyte size. Based on these findings, we propose that the genetic alteration of the NKA/Cav1 regulatory path uncovered in human iAdi leads to lipodystrophy in mice.NEW & NOTEWORTHY A Na/K-ATPase α1 caveolin-binding motif regulates adipogenesis. Mutation of this binding motif in the mouse leads to reduced fat with increased extracellular matrix production and inflammation. RNA-seq analysis and pharmacological interventions in human iPSC-derived adipocytes revealed that TGF-β signal, rather than Na/K-ATPase-mediated ion transport, is a key mediator of NKA regulation of adipogenesis.
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Affiliation(s)
- Minqi Huang
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
| | - Xiaoliang Wang
- Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States
| | - Yiliang Chen
- Versiti Blood Research Institute, Milwaukee, West Virginia, United States
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Marco T Pessoa
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
| | - Kayleigh C Terrell
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
| | - Jue Zhang
- Versiti Blood Research Institute, Milwaukee, West Virginia, United States
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Jiang Tian
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
- Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States
| | - Zijian Xie
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
| | - Sandrine V Pierre
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
| | - Liquan Cai
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States
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Luo J, Zhang M, Chen Y, Zhang G, Zhou T, Kang L, Chen X, Guan H. Comprehensive analysis of the miRNA-mRNA regulatory network involved in spontaneous recovery of an H 2O 2-induced zebrafish cataract model. Exp Eye Res 2024; 240:109820. [PMID: 38340946 DOI: 10.1016/j.exer.2024.109820] [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: 09/27/2023] [Revised: 01/31/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024]
Abstract
OBJECTIVE To identify the hub miRNAs and mRNAs contributing to the spontaneous recovery of an H2O2-induced zebrafish cataract model. METHODS Zebrafishes were divided into three groups, i.e., Group A, which included normal control fish (day 0), and Groups B and C, where fish were injected with 2.5% hydrogen peroxide into the anterior chamber and reared for 14 and 30 days, respectively. Fish eyes were examined by stereomicroscope photography and optical coherence tomography (OCT). RNA profiles of fish lenses were detected by RNA sequencing. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) were identified among three groups. The DEGs and DEmiRs, which changed in opposite positions between "B vs. A" and "C vs. B" were defined as ODGs (opposite positions changed DEGs) and ODmiRs (opposite positions changed DEmiRs). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analysis were carried out by R language. The protein-protein interaction network (PPI) was constructed using STRING. Potential targets of miRNAs were obtained using miRanda. miRNA-mRNA networks were constructed by Cytoscape. RESULTS The fish lens opacity formed on day 14 and recovered to transparent on day 30 after injection. Compared to group B, 1366 DEGs and 54 DEmiRs were identified in group C. "C vs. B" DEGs were enriched in gene clusters related to development and oxidative phosphorylation. Target genes of DEmiRs were enriched in clusters such as development and cysteine metabolism. Among three groups, 786 ODGs and 27 ODmiRs were identified, and 480 ODGs were predicted as targets of ODmiRs. Target ODGs were enriched in pathways related to methionine metabolism, ubiquitin, sensory system development, and structural constituents of the eye lens. In addition, we established an ODmiRs-ODGs regulation network. CONCLUSION We identified several hub mRNAs and altered miRNAs in the formation and reversal of zebrafish cataracts. These hub miRNAs/mRNAs could be potential targets for the non-surgical treatment of ARC.
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Affiliation(s)
- Jiawei Luo
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Mu Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Yanhua Chen
- Nantong Center for Disease Control and Prevention, Nantong, 226001, Jiangsu, China
| | - Guowei Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Tianqiu Zhou
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Lihua Kang
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Xiaoqing Chen
- Department of Party Committee Personnel Work, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Huaijin Guan
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China.
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Adeva-Andany MM, Domínguez-Montero A, Adeva-Contreras L, Fernández-Fernández C, Carneiro-Freire N, González-Lucán M. Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases. Curr Diabetes Rev 2024; 20:e160823219824. [PMID: 37587805 DOI: 10.2174/1573399820666230816111624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/28/2023] [Accepted: 05/31/2023] [Indexed: 08/18/2023]
Abstract
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Alberto Domínguez-Montero
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | - Carlos Fernández-Fernández
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Natalia Carneiro-Freire
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Manuel González-Lucán
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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Neuhaus M, Fryklund C, Taylor H, Borreguero-Muñoz A, Kopietz F, Ardalani H, Rogova O, Stirrat L, Bremner SK, Spégel P, Bryant NJ, Gould GW, Stenkula KG. EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events. Mol Biol Cell 2023; 34:ar124. [PMID: 37703099 PMCID: PMC10846623 DOI: 10.1091/mbc.e23-03-0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/14/2023] Open
Abstract
Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.
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Affiliation(s)
- Mathis Neuhaus
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | - Claes Fryklund
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | - Holly Taylor
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | | | - Franziska Kopietz
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | - Hamidreza Ardalani
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, 22241 Lund, Sweden
| | - Oksana Rogova
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, 22241 Lund, Sweden
| | - Laura Stirrat
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | - Shaun K. Bremner
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | - Peter Spégel
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, 22241 Lund, Sweden
| | - Nia J. Bryant
- Department of Biology and York Biomedical Research Institute, University of York, York YO10 5DD, UK
| | - Gwyn W. Gould
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | - Karin G. Stenkula
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Tan Y, Song Q. Research trends and hotspots on the links between caveolin and cancer: bibliometric and visual analysis from 2003 to 2022. Front Pharmacol 2023; 14:1237456. [PMID: 37576808 PMCID: PMC10416243 DOI: 10.3389/fphar.2023.1237456] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/21/2023] [Indexed: 08/15/2023] Open
Abstract
Introduction: Extensive studies indicated that caveolin is a key regulator in multiple cellular processes. Recently, growing evidence demonstrated that caveolin is critically involved in tumor progression. Since no relevant bibliometric study has been published, we performed a bibliometric and visual analysis to depict the knowledge framework of research related to the involvement of caveolin in cancer. Methods: Relevant studies published in English during 2003-2022 were obtained from the Web of Science Core Collection database. Three programs (VOSviewer, CiteSpace, and R-bibliometrix) and the website of bibliometrics (http://bibliometric.com/) were applied to construct networks based on the analysis of countries, institutions, authors, journals, references, and keywords. Results: A total of 2,463 documents were extracted and identified. The United States had the greatest number of publications and total citations, and Thomas Jefferson University was the most productive institution. Michael P. Lisanti was the most influential scholar in this research domain. Cell Cycle was the journal with the most publications on this subject. The most local-cited document was the article titled "Caveolin-1 in oncogenic transformation, cancer, and metastasis." A comprehensive analysis has been conducted based on keywords and cited references. Initially, the research frontiers were predominantly "signal transduction", "human breast cancer," "oncogenically transformed cells," "tumor suppressor gene," and "fibroblasts." While in recent years, the research emphasis has shifted to "tumor microenvironment," "epithelial mesenchymal transition," "nanoparticles," and "stem cells." Conclusion: Taken together, our bibliometric analysis shows that caveolin continues to be of interest in cancer research. The hotspots and research frontiers have evolved from the regulation of cancer signaling, to potential targets of cancer therapy and novel techniques. These results can provide a data-based reference for the guidance of future research.
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Affiliation(s)
- Yaqian Tan
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qi Song
- Department of Pharmacy, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
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Han B, Gulsevin A, Connolly S, Wang T, Meyer B, Porta J, Tiwari A, Deng A, Chang L, Peskova Y, Mchaourab HS, Karakas E, Ohi MD, Meiler J, Kenworthy AK. Structural analysis of the P132L disease mutation in caveolin-1 reveals its role in the assembly of oligomeric complexes. J Biol Chem 2023; 299:104574. [PMID: 36870682 PMCID: PMC10124911 DOI: 10.1016/j.jbc.2023.104574] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 01/09/2023] [Accepted: 02/03/2023] [Indexed: 03/06/2023] Open
Abstract
Caveolin-1 (CAV1) is a membrane-sculpting protein that oligomerizes to generate flask-shaped invaginations of the plasma membrane known as caveolae. Mutations in CAV1 have been linked to multiple diseases in humans. Such mutations often interfere with oligomerization and the intracellular trafficking processes required for successful caveolae assembly, but the molecular mechanisms underlying these defects have not been structurally explained. Here, we investigate how a disease-associated mutation in one of the most highly conserved residues in CAV1, P132L, affects CAV1 structure and oligomerization. We show that P132 is positioned at a major site of protomer-protomer interactions within the CAV1 complex, providing a structural explanation for why the mutant protein fails to homo-oligomerize correctly. Using a combination of computational, structural, biochemical, and cell biological approaches, we find that despite its homo-oligomerization defects P132L is capable of forming mixed hetero-oligomeric complexes with WT CAV1 and that these complexes can be incorporated into caveolae. These findings provide insights into the fundamental mechanisms that control the formation of homo- and hetero-oligomers of caveolins that are essential for caveolae biogenesis, as well as how these processes are disrupted in human disease.
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Affiliation(s)
- Bing Han
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Alican Gulsevin
- Department of Chemistry, Vanderbilt University, Nashville, TN, USA
| | - Sarah Connolly
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Ting Wang
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Brigitte Meyer
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Jason Porta
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Ajit Tiwari
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Angie Deng
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Louise Chang
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Yelena Peskova
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Hassane S Mchaourab
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Erkan Karakas
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Melanie D Ohi
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Jens Meiler
- Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Institute for Drug Discovery, Leipzig University, Leipzig, Germany
| | - Anne K Kenworthy
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA.
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Sotodosos-Alonso L, Pulgarín-Alfaro M, Del Pozo MA. Caveolae Mechanotransduction at the Interface between Cytoskeleton and Extracellular Matrix. Cells 2023; 12:cells12060942. [PMID: 36980283 PMCID: PMC10047380 DOI: 10.3390/cells12060942] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
The plasma membrane (PM) is subjected to multiple mechanical forces, and it must adapt and respond to them. PM invaginations named caveolae, with a specific protein and lipid composition, play a crucial role in this mechanosensing and mechanotransduction process. They respond to PM tension changes by flattening, contributing to the buffering of high-range increases in mechanical tension, while novel structures termed dolines, sharing Caveolin1 as the main component, gradually respond to low and medium forces. Caveolae are associated with different types of cytoskeletal filaments, which regulate membrane tension and also initiate multiple mechanotransduction pathways. Caveolar components sense the mechanical properties of the substrate and orchestrate responses that modify the extracellular matrix (ECM) according to these stimuli. They perform this function through both physical remodeling of ECM, where the actin cytoskeleton is a central player, and via the chemical alteration of the ECM composition by exosome deposition. Here, we review mechanotransduction regulation mediated by caveolae and caveolar components, focusing on how mechanical cues are transmitted through the cellular cytoskeleton and how caveolae respond and remodel the ECM.
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Affiliation(s)
- Laura Sotodosos-Alonso
- Mechanoadaptation and Caveolae Biology Laboratory, Novel Mechanisms of Atherosclerosis Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Marta Pulgarín-Alfaro
- Mechanoadaptation and Caveolae Biology Laboratory, Novel Mechanisms of Atherosclerosis Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Miguel A Del Pozo
- Mechanoadaptation and Caveolae Biology Laboratory, Novel Mechanisms of Atherosclerosis Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
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10
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Ganekal P, Vastrad B, Kavatagimath S, Vastrad C, Kotrashetti S. Bioinformatics and Next-Generation Data Analysis for Identification of Genes and Molecular Pathways Involved in Subjects with Diabetes and Obesity. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59020309. [PMID: 36837510 PMCID: PMC9967176 DOI: 10.3390/medicina59020309] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/19/2023] [Accepted: 01/29/2023] [Indexed: 02/10/2023]
Abstract
Background and Objectives: A subject with diabetes and obesity is a class of the metabolic disorder. The current investigation aimed to elucidate the potential biomarker and prognostic targets in subjects with diabetes and obesity. Materials and Methods: The next-generation sequencing (NGS) data of GSE132831 was downloaded from Gene Expression Omnibus (GEO) database. Functional enrichment analysis of DEGs was conducted with ToppGene. The protein-protein interactions network, module analysis, target gene-miRNA regulatory network and target gene-TF regulatory network were constructed and analyzed. Furthermore, hub genes were validated by receiver operating characteristic (ROC) analysis. A total of 872 DEGs, including 439 up-regulated genes and 433 down-regulated genes were observed. Results: Second, functional enrichment analysis showed that these DEGs are mainly involved in the axon guidance, neutrophil degranulation, plasma membrane bounded cell projection organization and cell activation. The top ten hub genes (MYH9, FLNA, DCTN1, CLTC, ERBB2, TCF4, VIM, LRRK2, IFI16 and CAV1) could be utilized as potential diagnostic indicators for subjects with diabetes and obesity. The hub genes were validated in subjects with diabetes and obesity. Conclusion: This investigation found effective and reliable molecular biomarkers for diagnosis and prognosis by integrated bioinformatics analysis, suggesting new and key therapeutic targets for subjects with diabetes and obesity.
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Affiliation(s)
- Prashanth Ganekal
- Department of General Medicine, Basaveshwara Medical College, Chitradurga 577501, Karnataka, India
| | - Basavaraj Vastrad
- Department of Pharmaceutical Chemistry, K.L.E. College of Pharmacy, Gadag 582101, Karnataka, India
| | - Satish Kavatagimath
- Department of Pharmacognosy, K.L.E. College of Pharmacy, Belagavi 590010, Karnataka, India
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India
- Correspondence: ; Tel.: +91-9480073398
| | - Shivakumar Kotrashetti
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India
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11
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Aslanyan MG, Doornbos C, Diwan GD, Anvarian Z, Beyer T, Junger K, van Beersum SEC, Russell RB, Ueffing M, Ludwig A, Boldt K, Pedersen LB, Roepman R. A targeted multi-proteomics approach generates a blueprint of the ciliary ubiquitinome. Front Cell Dev Biol 2023; 11:1113656. [PMID: 36776558 PMCID: PMC9908615 DOI: 10.3389/fcell.2023.1113656] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/17/2023] [Indexed: 01/27/2023] Open
Abstract
Establishment and maintenance of the primary cilium as a signaling-competent organelle requires a high degree of fine tuning, which is at least in part achieved by a variety of post-translational modifications. One such modification is ubiquitination. The small and highly conserved ubiquitin protein possesses a unique versatility in regulating protein function via its ability to build mono and polyubiquitin chains onto target proteins. We aimed to take an unbiased approach to generate a comprehensive blueprint of the ciliary ubiquitinome by deploying a multi-proteomics approach using both ciliary-targeted ubiquitin affinity proteomics, as well as ubiquitin-binding domain-based proximity labelling in two different mammalian cell lines. This resulted in the identification of several key proteins involved in signaling, cytoskeletal remodeling and membrane and protein trafficking. Interestingly, using two different approaches in IMCD3 and RPE1 cells, respectively, we uncovered several novel mechanisms that regulate cilia function. In our IMCD3 proximity labeling cell line model, we found a highly enriched group of ESCRT-dependent clathrin-mediated endocytosis-related proteins, suggesting an important and novel role for this pathway in the regulation of ciliary homeostasis and function. In contrast, in RPE1 cells we found that several structural components of caveolae (CAV1, CAVIN1, and EHD2) were highly enriched in our cilia affinity proteomics screen. Consistently, the presence of caveolae at the ciliary pocket and ubiquitination of CAV1 specifically, were found likely to play a role in the regulation of ciliary length in these cells. Cilia length measurements demonstrated increased ciliary length in RPE1 cells stably expressing a ubiquitination impaired CAV1 mutant protein. Furthermore, live cell imaging in the same cells revealed decreased CAV1 protein turnover at the cilium as the possible cause for this phenotype. In conclusion, we have generated a comprehensive list of cilia-specific proteins that are subject to regulation via ubiquitination which can serve to further our understanding of cilia biology in health and disease.
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Affiliation(s)
- Mariam G. Aslanyan
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Cenna Doornbos
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Gaurav D. Diwan
- BioQuant, Heidelberg University, Heidelberg, Germany
- Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany
| | - Zeinab Anvarian
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Tina Beyer
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Katrin Junger
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Sylvia E. C. van Beersum
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Robert B. Russell
- BioQuant, Heidelberg University, Heidelberg, Germany
- Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany
| | - Marius Ueffing
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Alexander Ludwig
- School of Biological Sciences, NTU Institute of Structural Biology, Nanyang Technological University, Singapore City, Singapore
| | - Karsten Boldt
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Lotte B. Pedersen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Ronald Roepman
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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12
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Shi M, Yang S, Huang X, Wang S, Li W, Yun J, Lu C, Yang Y, Cai C, Gao P, Guo X, Li B, Cao G. Caveolae-associated protein 3 promotes adipogenic differentiation of porcine preadipocytes by promoting extracellular signal-regulated kinase phosphorylation. Anim Sci J 2023; 94:e13822. [PMID: 36922373 DOI: 10.1111/asj.13822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 02/03/2023] [Accepted: 02/16/2023] [Indexed: 03/18/2023]
Abstract
Fat deposition is one of the key factors affecting the economic development of pig husbandry. The aim of this study was to investigate the expression characteristics of caveolae-associated protein 3 (CAVIN3) and to elucidate its effect and mechanism on adipogenic differentiation of porcine preadipocytes. Cell transfection, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and oil red O staining were used to detect the effect of CAVIN3 on the differentiation of porcine preadipocytes. The results showed that CAVIN3 was expressed in various tissues, with higher expression in adipose tissue, differentially expressed during cell adipogenic differentiation, and mainly distributed in the cytoplasm. Functional studies showed that, after CAVIN3 interference in preadipocytes, the expression of adipogenic factors and the content of lipid droplets were significantly decreased (p < 0.05). The results were reversed after CAVIN3 was overexpressed. The mechanism research showed that LY3214996 inhibited the extracellular signal-regulated kinase (ERK) phosphorylation and further inhibited lipogenic factors expression. Overexpression of CAVIN3 attenuates the inhibitory effect of LY3214996 on ERK phosphorylation and attenuates its inhibitory effect on adipogenic differentiation. Therefore, this study demonstrated that CAVIN3 promotes the differentiation of porcine preadipocytes by promoting ERK phosphorylation. The present study can lay a theoretical foundation for further studying the molecular mechanism of porcine fat deposition.
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Affiliation(s)
- Mingyue Shi
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Shuai Yang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Xiaoyu Huang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Shouyuan Wang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Wenxia Li
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Jiale Yun
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Chang Lu
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Yang Yang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Chunbo Cai
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Pengfei Gao
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Xiaohong Guo
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Bugao Li
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Guoqing Cao
- College of Animal Science, Shanxi Agricultural University, Taigu, China
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Aboy-Pardal MC, Jimenez-Carretero D, Terrés-Domínguez S, Pavón DM, Sotodosos-Alonso L, Jiménez-Jiménez V, Sánchez-Cabo F, Del Pozo MA. A deep learning-based tool for the automated detection and analysis of caveolae in transmission electron microscopy images. Comput Struct Biotechnol J 2022; 21:224-237. [PMID: 36544477 PMCID: PMC9755247 DOI: 10.1016/j.csbj.2022.11.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/29/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Caveolae are nanoscopic and mechanosensitive invaginations of the plasma membrane, essential for adipocyte biology. Transmission electron microscopy (TEM) offers the highest resolution for caveolae visualization, but provides complicated images that are difficult to classify or segment using traditional automated algorithms such as threshold-based methods. As a result, the time-consuming tasks of localization and quantification of caveolae are currently performed manually. We used the Keras library in R to train a convolutional neural network with a total of 36,000 TEM image crops obtained from adipocytes previously annotated manually by an expert. The resulting model can differentiate caveolae from non-caveolae regions with a 97.44% accuracy. The predictions of this model are further processed to obtain caveolae central coordinate detection and cytoplasm boundary delimitation. The model correctly finds negligible caveolae predictions in images from caveolae depleted Cav1-/- adipocytes. In large reconstructions of adipocyte sections, model and human performances are comparable. We thus provide a new tool for accurate caveolae automated analysis that could speed up and assist in the characterization of the cellular mechanical response.
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Affiliation(s)
- María C.M. Aboy-Pardal
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Daniel Jimenez-Carretero
- Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares
(CNIC), 28029 Madrid, Spain
| | - Sara Terrés-Domínguez
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Dácil M. Pavón
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Laura Sotodosos-Alonso
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Víctor Jiménez-Jiménez
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Fátima Sánchez-Cabo
- Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares
(CNIC), 28029 Madrid, Spain
| | - Miguel A. Del Pozo
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
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Abstract
PURPOSE OF REVIEW Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy. RECENT FINDINGS The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder. Diagnosis of lipodystrophy is mainly based upon physical examination findings of loss of body fat and can be supported by body composition analysis by skinfold measurements, dual-energy x-ray absorptiometry, and whole-body magnetic resonance imaging. Confirmatory genetic testing is helpful in the proband and at-risk family members with suspected genetic lipodystrophies. The treatment is directed towards the specific comorbidities and metabolic complications, and there is no treatment to reverse body fat loss. Metreleptin should be considered as the first-line therapy for metabolic complications in patients with generalized lipodystrophy and for prevention of comorbidities in children. Metformin and insulin therapy are the best options for treating hyperglycemia and fibrates and/or fish oil for hypertriglyceridemia. Lipodystrophy should be suspected in lean and muscular subjects presenting with diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver disease, polycystic ovarian syndrome, or amenorrhea. Diabetologists should be aware of lipodystrophies and consider genetic varieties as an important subtype of monogenic diabetes.
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Affiliation(s)
- Nivedita Patni
- Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Abhimanyu Garg
- Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8537, USA.
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15
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Tan Z, Halter B, Liu D, Gilbert ER, Cline MA. Dietary Flavonoids as Modulators of Lipid Metabolism in Poultry. Front Physiol 2022; 13:863860. [PMID: 35547590 PMCID: PMC9081441 DOI: 10.3389/fphys.2022.863860] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/07/2022] [Indexed: 01/04/2023] Open
Abstract
Flavonoids, naturally-occurring compounds with multiple phenolic structures, are the most widely distributed phytochemicals in the plant kingdom, and are mainly found in vegetables, fruits, grains, roots, herbs, and tea and red wine products. Flavonoids have health-promoting effects and are indispensable compounds in nutritional and pharmaceutical (i.e., nutraceutical) applications. Among the demonstrated bioactive effects of flavonoids are anti-oxidant, anti-inflammatory, and anti-microbial in a range of research models. Through dietary formulation strategies, numerous flavonoids provide the ability to support bird health while improving the nutritional quality of poultry meat and eggs by changing the profile of fatty acids and reducing cholesterol content. A number of such compounds have been shown to inhibit adipogenesis, and promote lipolysis and apoptosis in adipose tissue cells, and thereby have the potential to affect fat accretion in poultry at various ages and stages of production. Antioxidant and anti-inflammatory properties contribute to animal health by preventing free radical damage in tissues and ameliorating inflammation in adipose tissue, which are concerns in broiler breeders and laying hens. In this review, we summarize the progress in understanding the effects of dietary flavonoids on lipid metabolism and fat deposition in poultry, and discuss the associated physiological mechanisms.
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Affiliation(s)
- Zhendong Tan
- Department of Animal and Poultry Sciences, Blacksburg, VA, United States
| | - Bailey Halter
- Department of Animal and Poultry Sciences, Blacksburg, VA, United States
| | - Dongmin Liu
- Department of Human Nutrition, Foods, and Exercise, Blacksburg, VA, United States
| | | | - Mark A Cline
- Department of Animal and Poultry Sciences, Blacksburg, VA, United States
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16
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Iqbal J, Jiang HL, Wu HX, Li L, Zhou YH, Hu N, Xiao F, Wang T, Xu SN, Zhou HD. Hereditary severe insulin resistance syndrome: Pathogenesis, pathophysiology, and clinical management. Genes Dis 2022. [PMID: 37492723 PMCID: PMC10363564 DOI: 10.1016/j.gendis.2022.03.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.
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17
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Patni N, Hegele RA, Garg A. Caveolar dysfunction and lipodystrophies. Eur J Endocrinol 2022; 186:C1-C4. [PMID: 34935636 PMCID: PMC9285858 DOI: 10.1530/eje-21-1243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 01/30/2023]
Affiliation(s)
- Nivedita Patni
- Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Robert A Hegele
- Department of Medicine and Robarts Research Institute, Western University, London, Ontario, Canada
| | - Abhimanyu Garg
- Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas, USA
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18
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Low JY, Laiho M. Caveolae-Associated Molecules, Tumor Stroma, and Cancer Drug Resistance: Current Findings and Future Perspectives. Cancers (Basel) 2022; 14:cancers14030589. [PMID: 35158857 PMCID: PMC8833326 DOI: 10.3390/cancers14030589] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Cell membranes contain small invaginations called caveolae. They are a specialized lipid domain and orchestrate cellular signaling events, mechanoprotection, and lipid homeostasis. Formation of the caveolae depends on two classes of proteins, the caveolins and cavins, which form large complexes that allow their self-assembly into caveolae. Loss of either of these two proteins leads to distortion of the caveolae structure and disruption of many physiological processes that affect diseases of the muscle, metabolic states governing lipids, and the glucose balance as well as cancers. In cancers, the expression of caveolins and cavins is heterogenous, and they undergo alterations both in the tumors and the surrounding tumor microenvironment stromal cells. Remarkably, their expression and function has been associated with resistance to many cancer drugs. Here, we summarize the current knowledge of the resistance mechanisms and how this knowledge could be applied into the clinic in future. Abstract The discovery of small, “cave-like” invaginations at the plasma membrane, called caveola, has opened up a new and exciting research area in health and diseases revolving around this cellular ultrastructure. Caveolae are rich in cholesterol and orchestrate cellular signaling events. Within caveola, the caveola-associated proteins, caveolins and cavins, are critical components for the formation of these lipid rafts, their dynamics, and cellular pathophysiology. Their alterations underlie human diseases such as lipodystrophy, muscular dystrophy, cardiovascular disease, and diabetes. The expression of caveolins and cavins is modulated in tumors and in tumor stroma, and their alterations are connected with cancer progression and treatment resistance. To date, although substantial breakthroughs in cancer drug development have been made, drug resistance remains a problem leading to treatment failures and challenging translation and bench-to-bedside research. Here, we summarize the current progress in understanding cancer drug resistance in the context of caveola-associated molecules and tumor stroma and discuss how we can potentially design therapeutic avenues to target these molecules in order to overcome treatment resistance.
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Affiliation(s)
- Jin-Yih Low
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
- Correspondence: ; Tel.: +1-410-502-9748; Fax: +1-410-502-2821
| | - Marikki Laiho
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Higuchi Y, Ogata T, Nakanishi N, Nishi M, Sakamoto A, Tsuji Y, Tomita S, Matoba S. Requirement of Cavin-2 for the expression and stability of IRβ in adequate adipocyte differentiation. Mol Metab 2021; 55:101416. [PMID: 34896640 PMCID: PMC8728525 DOI: 10.1016/j.molmet.2021.101416] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/29/2021] [Accepted: 12/07/2021] [Indexed: 12/22/2022] Open
Abstract
Objective Adipogenesis plays an essential role in maintaining energy and hormonal balance. Cavin-2, one of the caveolae-related proteins, is abundant in adipocytes, the leading site of adipogenesis. However, the details of the roles of Cavin-2 in adipogenesis remain unknown. Here, we demonstrate the requirement of Cavin-2 for the expression and stability of IRβ in adequate adipocyte differentiation. Methods Cavin-2 knockout (Cavin-2 KO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 8 weeks. We evaluated body weight, food intake, and several tissues. Glucose homeostasis was assessed by glucose and insulin tolerance tests. Insulin signaling in epididymal white adipose tissue (eWAT) was determined by Akt phosphorylation. In vitro study, we evaluated adipocyte differentiation, adipogenesis-related genes, and insulin signaling to clarify the relationship between Cavin-2 and adipogenesis under the manipulation of Cavin-2 expression. Results Caveolae structure decreased in eWAT of Cavin-2 KO mice and Cavin-2 knockdown 3T3-L1 cells. Cavin-2 enhanced the stability of insulin receptor (IR) through direct association at the plasma membrane in adipocytes, resulting in accelerated insulin/IR/Akt signaling-induced adipogenic gene expression in insulin-containing solution-stimulated 3T3-L1 adipocytes. IR-mediated Akt activation also enhanced Cavin-2 and IR expression. Cavin-2 knockout mice showed insulin resistance with dyslipidemia and pathological hypertrophic adipocytes after a HFD. Conclusions Cavin-2 enhances IR stability through binding IR and regulates insulin signaling, promoting adequate adipocyte differentiation. Our findings highlight the pivotal role of Cavin-2 in adipogenesis and lipid metabolism, which may help to develop novel therapies for pathological obesity and adipogenic disorders.
Cavin-2 expression is increased progressively during adipocyte differentiation. Cavin-2 knockout shows little caveolae in 3T3L-1 adipocytes and eWAT of mice. Cavin-2 positively regulates adipogenesis through IR stabilization. Cavin-2 knockout mice with a high-fat diet show insulin resistance and dyslipidemia.
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Affiliation(s)
- Yusuke Higuchi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takehiro Ogata
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; Department of Pathology and Cell Regulation, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Naohiko Nakanishi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Masahiro Nishi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Akira Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yumika Tsuji
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shinya Tomita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Fryklund C, Morén B, Shah S, Grossi M, Degerman E, Matthaeus C, Stenkula KG. EH Domain-Containing 2 Deficiency Restricts Adipose Tissue Expansion and Impairs Lipolysis in Primary Inguinal Adipocytes. Front Physiol 2021; 12:740666. [PMID: 34630160 PMCID: PMC8497890 DOI: 10.3389/fphys.2021.740666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/25/2021] [Indexed: 11/21/2022] Open
Abstract
Lipid uptake can be facilitated via caveolae, specific plasma membrane invaginations abundantly expressed in adipocytes. The dynamin-related protein EH domain-containing 2 (EHD2) stabilizes caveolae at the cell surface. Here, we have examined the importance of EHD2 for lipid handling using primary adipocytes isolated from EHD2 knockout (Ehd2−/−) C57BL6/N mice. Following high-fat diet (HFD) feeding, we found a clear impairment of epididymal, but not inguinal, adipose tissue expansion in Ehd2−/− compared with Ehd2+/+ (WT) mice. Cell size distribution analysis revealed that Ehd2−/− mice had a lower proportion of small adipocytes, and an accumulation of medium-sized adipocytes in both epididymal and inguinal adipose tissue. Further, PPARγ activity, FABP4 and caveolin-1 expression were decreased in adipocytes isolated from Ehd2−/− mice. Inguinal adipocytes isolated from Ehd2−/− mice displayed reduced lipolysis in response to beta adrenergic receptor agonist, which was associated with reduced phosphorylation of perilipin-1 and hormone sensitive lipase (HSL). This impairment could not be rescued using a cAMP analog, indicating that impaired lipolysis in Ehd2−/− primary adipocytes likely occurs at the level of, or downstream of, protein kinase A (PKA). Altogether, these findings pinpoint the importance of EHD2 for maintained intracellular lipid metabolism, and emphasize differences in mechanisms regulating lipid handling in various adipose-tissue depots.
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Affiliation(s)
- Claes Fryklund
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Björn Morén
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Shrenika Shah
- School of Biomedical, Nutritional and Sport Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Mario Grossi
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Eva Degerman
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Claudia Matthaeus
- National Heart, Lung and Blood Institute, NIH, Bethesda, MD, United States
| | - Karin G Stenkula
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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21
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Jéru I. Genetics of lipodystrophy syndromes. Presse Med 2021; 50:104074. [PMID: 34562561 DOI: 10.1016/j.lpm.2021.104074] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/24/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open
Abstract
Lipodystrophic syndromes (LS) constitute a clinically and genetically heterogeneous group of diseases characterized by a loss of adipose tissue. These syndromes are usually associated with metabolic complications, which are determinant for morbidity and mortality. The classical forms of LS include partial, generalized, and progeroid lipodystrophies. They are usually due to defects in proteins playing a key role in adipogenesis and adipocyte functions. More recently, systemic disorders combining lipodystrophy and multiple organ dysfunction have been described, including autoinflammatory syndromes, mitochondrial disorders, as well as other complex entities. To date, more than thirty genes have been implicated in the monogenic forms of LS, but the majority of them remain genetically-unexplained. The associated pathophysiological mechanisms also remain to be clarified in many instances. Next generation sequencing-based approaches allow simultaneous testing of multiple genes and have become crucial to speed up the identification of new disease-causing genes. The challenge for geneticists is now the interpretation of the amount of available genetic data, generated especially by exome and whole-genome sequencing. International recommendations on the interpretation and classification of variants have been set up and are regularly reassessed. Very close collaboration between geneticists, clinicians, and researchers will be necessary to make rapid progress in understanding the molecular and cellular basis of these diseases, and to promote personalized medicine.
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Affiliation(s)
- Isabelle Jéru
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France.
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22
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Khatibi N, Mirzababaei A, Shiraseb F, Abaj F, Koohdani F, Mirzaei K. Interactions between caveolin 1 polymorphism and the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND) diet on metabolic dyslipidemia in overweight and obese adult women: a cross-sectional study. BMC Res Notes 2021; 14:364. [PMID: 34544501 PMCID: PMC8454002 DOI: 10.1186/s13104-021-05777-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/07/2021] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The increased prevalence of metabolic dyslipidemia (MD) and its association with a variety of disorders raised a lot of attention to its management. Caveolin 1 (CAV1) the key protein in the caval structure of plasma membranes is many cell types that play an important role in its function. (CAV1) is a known gene associated with obesity. Today, a novel diet recognized as the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND) is reported to have a positive effect on overall health. Hence, we aimed to investigate the interactions between CAV1 polymorphism and MIND diet on the MD in overweight and obese patients. RESULTS Remarkably, there was a significant interaction between the MIND diet and CAV1 rs3807992 for dyslipidemia (β = - 0.25 ± 132, P = 0.05) in the crude model. Whereby, subjects with dominant alleles had a lower risk of dyslipidemia and risk allele carriers with higher adherence to the MIND diet may exhibit the lower dyslipidemia. This study presented the CAV1 gene as a possible genetic marker in recognizing people at higher risks for metabolic diseases. It also indicated that using the MIND diet may help in improving dyslipidemia through providing a probable interaction with CAV1 rs3807992 polymorphism.
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Affiliation(s)
- Nasim Khatibi
- Shahid Sadoughi University of Medical Science, Yazd, Iran
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Farideh Shiraseb
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Fariba Koohdani
- Department of Cellular, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Molecular Nutrition, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran.
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23
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Zhang Y, Yuan H, Peng M, Hu Z, Fan Z, Xu J, He L, Wang Y, Wang W, Su Y, Liu C, Zhang H, Zhao K. Folic acid deficiency damages male reproduction via endoplasmic reticulum stress-associated PERK pathway induced by Caveolin-1 in mice. Syst Biol Reprod Med 2021; 67:383-394. [PMID: 34474604 DOI: 10.1080/19396368.2021.1954724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Folic acid is critical to maintaining normal male reproductive function. Endoplasmic reticulum (ER) stress plays a crucial role in folic acid deficiency. Studies have shown that Caveolin-1 (Cav-1) is involved in ER stress, but the specific mechanism in male reproduction is still unclear. This study aimed to investigate the effects of folic acid deficiency on spermatogenesis and elucidate the underlying mechanisms. C57BL/6 mice fed with folic acid deficiency induced diet(0.3 mg/kg) were used. A significant decrease in the sperm concentration in the folic acid deficiency group was observed. Meanwhile, folic acid deficiency decreased Cav-1 expression in the testis tissue and increased endoplasmic reticulum stress-related PERK, eIF2α, ATF4, CHOP gene expression. Our results suggest that folic acid deficiency can affect male reproduction through the Cav-1-PERK-eIFα-ATF4-CHOP pathway.Abbreviations: ATF4: activating transcription factor 4; Ca2+: calcium ion; Cav-1: Caveolin-1; CCK-8: cell counting kit-8; CHOP: CCAAT-enhancer-binding protein homologous protein; DNA: Deoxyribonucleic acid; DSB: double strand breakage; eIF2α: eukaryotic Initiation Factor 2 alpha; ER: endoplasmic reticulum; FD: folic acid deficiency; FITC: fluorescein isothiocyanate; HE: hematoxylin and eosin; H3K4me3: histone H3 lysine 4 trimethylation; PERK: protein kinase RNA-like endoplasmic reticulum kinase; PI: propidium iodide; RT-qPCR: quantitative reverse transcription PCR; TUNEL: TdT mediated dUTP Nick End Labeling.
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Affiliation(s)
- Yuan Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongfang Yuan
- Department of Obstetrics And Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meilin Peng
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Hu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zunpan Fan
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Xu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liting He
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongfeng Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufang Su
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Liu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiping Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abaj F, Saeedy SAG, Mirzaei K. Mediation role of body fat distribution (FD) on the relationship between CAV1 rs3807992 polymorphism and metabolic syndrome in overweight and obese women. BMC Med Genomics 2021; 14:202. [PMID: 34384444 PMCID: PMC8359537 DOI: 10.1186/s12920-021-01050-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 08/03/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is associated with an increased risk of morbidity and mortality in almost all chronic diseases. The most frequent methods for the calculation of a continuous MetS (cMetS) score have used the standardized residuals in linear regression (z-score). Recently, emerging data suggest that one of the main genetic targets is the CAV1, which plays a crucial role in regulating body fat distribution. This study is designed to investigate the relationship between CAV1 rs3807992 genotypes and cMetS, and to determine whether body fat distribution plays a mediating role in this regard. METHODS The current cross-sectional study was conducted on 386 overweight and obese females. The CAV1 rs3807992 and body composition were measured by the PCR-RFLP method and bioelectrical impedance analysis, respectively. Serum profile of HDL-C, TGs, FPG, and Insulin were measured by standard protocols. RESULTS GG allele carriers had significantly lowered Z-MAP (p = 0.02), total cMetS (p = 0.03) and higher Z-HDL (p = 0.001) compared with (A) allele carriers. There was a significant specific indirect effect (standardized coefficient = 0.19; 95% CI 0.01-0.4) of Visceral fat level (VFL). Although, total body fat was significantly associated with CAV1 rs3807992 and cMetS, the specific indirect effect was not significant (standardized coefficient = 0.21; 95% CI - 0.006, 0.44). VFL contributed to significant indirect effects of 35% on the relationship between CAV1 and cMetS. CONCLUSION Higher visceral adipose tissue may affect the relationship between CAV1 and cMetS. Although CAV1 rs3807992 is linked to VFL in our study, the influence of this polymorphism on MetS is not via total fat.
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Affiliation(s)
- Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
| | | | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
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Abaj F, Saeedy SAG, Mirzaei K. Are caveolin-1 minor alleles more likely to be risk alleles in insulin resistance mechanisms in metabolic diseases? BMC Res Notes 2021; 14:185. [PMID: 34001235 PMCID: PMC8130340 DOI: 10.1186/s13104-021-05597-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 05/05/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Obesity and insulin resistance (IR) are interrelated in a range of ways. The IR-obesity relationship is not a cause-and-effect association. Molecular biology research has made tremendous strides in discovering contributors to find this association. Genes that control adipocyte function such as caveolin-1 (CAV1); probably interact in the pathogenesis of human IR in this context. The involvement of CAV1 in glucose/lipid homeostasis is revealed and could modify the signaling of the insulin receptor. We examined the association between CAV1 and insulin signaling in modifying dyslipidemia and fat composition in overweight and obese women with a prevalent variant in the CAV1 gene. RESULTS Minor allele carriers were slightly older and had higher BMI (p = 0.02), FMI (p = 0.006), and VLF (p = 0.01) values; and tended to have lower total cholesterol TC (p = 0.04), low-density lipoprotein cholesterol (LDL-C) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). HOMA-IR levels predicted fat mass index (FMI) 0.47 (0.08, 0.87), visceral fat level (VFL) 0.65 (0.23, 1.07), TC 6.82 (1.76, 11.88) and HDL-C - 1.663 (- 3.11, - 0.214) only between minor allele carriers in adjusted models. (β, CI). Our results cast a new light on the IR mechanism and future studies will elucidate the clinical relevance of CAV1-IR in patients with dyslipidemia and high fat composition.
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Affiliation(s)
- Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), No. 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, P.O. Box, 14155-6117, Tehran, Iran
| | | | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), No. 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, P.O. Box, 14155-6117, Tehran, Iran.
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26
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Araújo de Melo Campos JT, Dantas de Medeiros JL, Cardoso de Melo ME, Alvares da Silva M, Oliveira de Sena M, Sales Craveiro Sarmento A, Fassarella Agnez Lima L, de Freitas Fregonezi GA, Gomes Lima J. Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166120. [PMID: 33713793 DOI: 10.1016/j.bbadis.2021.166120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 01/17/2023]
Abstract
Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.
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Affiliation(s)
- Julliane Tamara Araújo de Melo Campos
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
| | - Jorge Luiz Dantas de Medeiros
- PneumoCardioVascular Lab/HUOL, Hospital Universitário Onofre Lopes, Empresa Brasileira de Serviços Hospitalares and Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
| | - Maria Eduarda Cardoso de Melo
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Monique Alvares da Silva
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Matheus Oliveira de Sena
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Aquiles Sales Craveiro Sarmento
- Unidade de Laboratório de Análises Clínicas e Anatomia Patológica, Hospital Universitário de Lagarto (HUL)/UFS, Lagarto, SE, Brazil
| | - Lucymara Fassarella Agnez Lima
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Guilherme Augusto de Freitas Fregonezi
- PneumoCardioVascular Lab/HUOL, Hospital Universitário Onofre Lopes, Empresa Brasileira de Serviços Hospitalares and Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil; Laboratório de Inovação Tecnológica em Reabilitação, Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Josivan Gomes Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL)/UFRN, Natal, RN, Brazil
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García JG, Ansorena E, Milagro FI, Zalba G, de Miguel C. Endothelial Nox5 Expression Modulates Glucose Uptake and Lipid Accumulation in Mice Fed a High-Fat Diet and 3T3-L1 Adipocytes Treated with Glucose and Palmitic Acid. Int J Mol Sci 2021; 22:ijms22052729. [PMID: 33800461 PMCID: PMC7962974 DOI: 10.3390/ijms22052729] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 12/14/2022] Open
Abstract
Obesity is a global health issue associated with insulin resistance and altered lipid homeostasis. It has been described that reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity are involved in the development of these pathologies. The present study describes the role of endothelial NOX5 expression over adipose tissue by using two experimental systems: NOX5 conditional knock-in mice fed with a high-fat diet and 3T3-L1 adipocytes cultured with conditioned media of NOX5-expressing endothelial cells previously treated with glucose and palmitic acid. Animals expressing NOX5 presented lower body weight gain and less mesenteric and epididymal adipose mass compared to control mice fed with the same diet. NOX5-expressing mice also showed significantly lower glycaemia and improved insulin-induced glucose uptake. In addition, Glut4 and Caveolin 1 (Cav1) expression were significantly increased in the adipose tissue of these animals. Likewise, 3T3-L1 adipocytes treated with conditioned media from NOX5-expressing endothelial cells, incubated with high glucose and palmitic acid, presented a reduction in lipid accumulation and an increase in glucose uptake. Moreover, a significant increase in the expression of Glut4 and Cav1 was also detected in these cells. Taken together, all these data support that, in response to a highly caloric diet, NOX5 endothelial activity may regulate glucose sensitivity and lipid homeostasis in the adipose tissue.
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Affiliation(s)
- Jorge G. García
- Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain; (J.G.G.); (E.A.); (G.Z.)
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain;
| | - Eduardo Ansorena
- Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain; (J.G.G.); (E.A.); (G.Z.)
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain;
| | - Fermín I. Milagro
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain;
- Center for Nutrition Research, Department of Nutrition, Food Science, and Physiology, University of Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobm), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Guillermo Zalba
- Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain; (J.G.G.); (E.A.); (G.Z.)
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain;
| | - Carlos de Miguel
- Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain; (J.G.G.); (E.A.); (G.Z.)
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain;
- Correspondence: ; Tel.: +34-948-425600 (ext. 806462)
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Abstract
Cellular senescence is a feature of most somatic cells. It is characterized by an irreversible cell cycle arrest and by the ability to secrete a plethora of mediators of inflammation and growth factors, which can alter the senescent cell's microenvironment. Senescent cells accumulate in tissues over time and contribute to both aging and the development of age-associated diseases. Senescent cells have antagonistic pleiotropic roles in cancer. Given the inability of senescent cells to proliferate, cellular senescence is a powerful tumor suppressor mechanism in young individuals. However, accumulation of senescent stromal cells during aging can fuel cancer cell growth in virtue of their capacity to release factors that stimulate cell proliferation. Caveolin-1 is a structural protein component of caveolae, invaginations of the plasma membrane involved in a variety of cellular processes, including signal transduction. Mounting evidence over the last 10-15 years has demonstrated a central role of caveolin-1 in the development of a senescent phenotype and the regulation of both the anti-tumorigenic and pro-tumorigenic properties of cellular senescence. In this review, we discuss the cellular mechanisms and functions of caveolin-1 in the context of cellular senescence and their relevance to the biology of cancer.
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Abstract
Caveolae are specialised and dynamic plasma membrane subdomains, involved in many cellular functions including endocytosis, signal transduction, mechanosensing and lipid storage, trafficking, and metabolism. Two protein families are indispensable for caveola formation and function, namely caveolins and cavins. Mutations of genes encoding these caveolar proteins cause serious pathological conditions such as cardiomyopathies, skeletal muscle diseases, and lipodystrophies. Deregulation of caveola-forming protein expression is associated with many types of cancers including prostate cancer. The distinct function of secretion of the prostatic fluid, and the unique metabolic phenotype of prostate cells relying on lipid metabolism as a main bioenergetic pathway further suggest a significant role of caveolae and caveolar proteins in prostate malignancy. Accumulating in vitro, in vivo, and clinical evidence showed the association of caveolin-1 with prostate cancer grade, stage, metastasis, and drug resistance. In contrast, cavin-1 was found to exhibit tumour suppressive roles. Studies on prostate cancer were the first to show the distinct function of the caveolar proteins depending on their localisation within the caveolar compartment or as cytoplasmic or secreted proteins. In this review, we summarise the roles of caveola-forming proteins in prostate cancer and the potential of exploiting them as therapeutic targets or biological markers.
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Caveolin-1, tetraspanin CD81 and flotillins in lymphocyte cell membrane organization, signaling and immunopathology. Biochem Soc Trans 2020; 48:2387-2397. [PMID: 33242069 DOI: 10.1042/bst20190387] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/24/2022]
Abstract
The adaptive immune system relies on B and T lymphocytes to ensure a specific and long-lasting protection of an individual from a wide range of potential pathogenic hits. Lymphocytes are highly potent and efficient in eliminating pathogens. However, lymphocyte activation must be tightly regulated to prevent incorrect activity that could result in immunopathologies, such as autoimmune disorders or cancers. Comprehensive insight into the molecular events underlying lymphocyte activation is of enormous importance to better understand the function of the immune system. It provides the basis to design therapeutics to regulate lymphocyte activation in pathological scenarios. Most reported defects in immunopathologies affect the regulation of intracellular signaling pathways. This highlights the importance of these molecules, which control lymphocyte activation and homeostasis impacting lymphocyte tolerance to self, cytokine production and responses to infections. Most evidence for these defects comes from studies of disease models in genetically engineered mice. There is an increasing number of studies focusing on lymphocytes derived from patients which supports these findings. Many indirectly involved proteins are emerging as unexpected regulators of the immune system. In this mini-review, we focus in proteins that regulate plasma membrane (PM) compartmentalization and thereby impact the steady state and the activation of immunoreceptors, namely the T cell antigen receptor (TCR) and the B cell antigen receptor (BCR). Some of these membrane proteins are shown to be involved in immune abnormalities; others, however, are not thoroughly investigated in the context of immune pathogenesis. We aim to highlight them and stimulate future research avenues.
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de Souza GM, de Albuquerque Borborema ME, de Lucena TMC, da Silva Santos AF, de Lima BR, de Oliveira DC, de Azevêdo Silva J. Caveolin-1 (CAV-1) up regulation in metabolic syndrome: all roads leading to the same end. Mol Biol Rep 2020; 47:9245-9250. [PMID: 33123955 DOI: 10.1007/s11033-020-05945-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/22/2020] [Indexed: 01/02/2023]
Abstract
Metabolic syndrome (MS) is a set of clinical conditions such as insulin resistance, hyperglycemia, systemic arterial hypertension (SAH), dyslipidemia, obesity and high abdominal circumference. Some of these clinical characteristics have been associated with caveolin-1, a caveolae structural protein, responsible for insulin activation, storage and degradation of cholesterol, and so on. Herein we assessed CAV-1 mRNA levels in MS patients comparing to healthy controls (HC) and according patients' clinical features. We included 87 patients in the study, 25 patients with MS, 30 patients with at least one clinical condition (diabetes, SAH, dyslipidemia, obesity and high abdominal circumference), 13 with two clinical conditions and 19 HC. CAV-1 mRNA levels from peripheral blood samples were assessed by Real Time qPCR using specific Taqman probe. The analysis was performed using ∆Cq method and the statistical tests Shapiro-Wilk, One-Way ANOVA and Mann-Whitney. We found CAV-1 increased mRNA levels in patients with MS (1.645 FC, p = 9.794 × 10-20) and even higher in patients with only one or two clinical conditions (2.215 FC, p = 1.215 × 10-32 and 1.716 FC, p = 4.197 × 10-05, respectively). When individual clinical conditions were observed, individuals with high abdominal circumference and obesity present a significantly up regulation when compared to HC (2.956 FC, p = 0.0004 and 3.643 FC, p = 0.002, respectively). This work indicates that CAV-1 gene expression from whole blood samples is associated to MS clinical conditions and may become a potential target for MS treatment and prevention.
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Affiliation(s)
- Gabriela Montenegro de Souza
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
| | - Maria Eduarda de Albuquerque Borborema
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Thays Maria Costa de Lucena
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Ariane Fernandes da Silva Santos
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Brenda Regina de Lima
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Dinaldo Cavalcanti de Oliveira
- Divisão de Cardiologia, Departamento de Medicina Clínica, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Jaqueline de Azevêdo Silva
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil.
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil.
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32
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Buwa N, Mazumdar D, Balasubramanian N. Caveolin1 Tyrosine-14 Phosphorylation: Role in Cellular Responsiveness to Mechanical Cues. J Membr Biol 2020; 253:509-534. [PMID: 33089394 DOI: 10.1007/s00232-020-00143-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
The plasma membrane is a dynamic lipid bilayer that engages with the extracellular microenvironment and intracellular cytoskeleton. Caveolae are distinct plasma membrane invaginations lined by integral membrane proteins Caveolin1, 2, and 3. Caveolae formation and stability is further supported by additional proteins including Cavin1, EHD2, Pacsin2 and ROR1. The lipid composition of caveolar membranes, rich in cholesterol and phosphatidylserine, actively contributes to caveolae formation and function. Post-translational modifications of Cav1, including its phosphorylation of the tyrosine-14 residue (pY14Cav1) are vital to its function in and out of caveolae. Cells that experience significant mechanical stress are seen to have abundant caveolae. They play a vital role in regulating cellular signaling and endocytosis, which could further affect the abundance and distribution of caveolae at the PM, contributing to sensing and/or buffering mechanical stress. Changes in membrane tension in cells responding to multiple mechanical stimuli affects the organization and function of caveolae. These mechanical cues regulate pY14Cav1 levels and function in caveolae and focal adhesions. This review, along with looking at the mechanosensitive nature of caveolae, focuses on the role of pY14Cav1 in regulating cellular mechanotransduction.
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Affiliation(s)
- Natasha Buwa
- Indian Institute of Science Education and Research, Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, India
| | - Debasmita Mazumdar
- Indian Institute of Science Education and Research, Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, India
| | - Nagaraj Balasubramanian
- Indian Institute of Science Education and Research, Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, India.
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Park PJ, Kim ST. Caveolae-Associated Protein 3 (Cavin-3) Influences Adipogenesis via TACE-Mediated Pref-1 Shedding. Int J Mol Sci 2020; 21:ijms21145000. [PMID: 32679831 PMCID: PMC7404391 DOI: 10.3390/ijms21145000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/06/2020] [Accepted: 07/13/2020] [Indexed: 12/16/2022] Open
Abstract
Abnormal adipogenesis regulation is accompanied by a variety of metabolic dysfunctions and disorders. Caveolae play an important role in the regulation of fat production, modulated by caveolae-associated proteins (Cavin-1 to 4). Here, we investigated the role of Cavin-3 in lipogenesis and adipocyte differentiation, as the regulatory functions and roles of Cavin-3 in adipocytes are unknown. A Cavin-3 knockdown/overexpression stable cell line was established, and adipogenesis-related gene and protein expression changes were investigated by real-time quantitative PCR and Western blot analysis, respectively. Additionally, confocal immune-fluorescence microscopy was used to verify the intracellular position of the relevant factors. The results showed that Cavin-3 mRNA and protein expression were elevated, along with physiological factors such as lipid droplet formation, during adipogenesis. Cavin-3 silencing resulted in retarded adipocyte differentiation, and its overexpression accelerated this process. Furthermore, Cavin-3 knockdown resulted in decreased expression of adipogenesis-related genes, such as PPAR-γ, FAS, aP2, and Adipoq, whereas preadipocyte factor-1 (Pref-1) was markedly increased during adipocyte maturation. Overall, Cavin-3 influences caveolar stability and modulates the tumor necrosis factor-alpha-converting enzyme (TACE)-mediated Pref-1 shedding process in both mouse and human adipocytes. The Cavin-3-dependent shedding mechanism appears to be an important process in adipocyte maturation, providing a potential therapeutic target for obesity-related disorders.
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Affiliation(s)
- Phil June Park
- Bioscience Laboratory, AMOREPACIFIC R&D Center, 1920 Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do 17074, Korea
- Correspondence: (P.J.P.); (S.T.K.); Tel.: +82-31-280-5639 (P.J.P.); +82-55-320-4038 (S.T.K.)
| | - Sung Tae Kim
- Department of Pharmaceutical Engineering, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do 50834, Korea
- Correspondence: (P.J.P.); (S.T.K.); Tel.: +82-31-280-5639 (P.J.P.); +82-55-320-4038 (S.T.K.)
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Abbasi M, Gupta VK, Chitranshi N, Gupta VB, Mirzaei M, Dheer Y, Garthwaite L, Zaw T, Parton RG, You Y, Graham SL. Caveolin-1 Ablation Imparts Partial Protection Against Inner Retinal Injury in Experimental Glaucoma and Reduces Apoptotic Activation. Mol Neurobiol 2020; 57:3759-3784. [PMID: 32578008 DOI: 10.1007/s12035-020-01948-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 05/13/2020] [Indexed: 12/16/2022]
Abstract
Retinal ganglion cell degeneration is a characteristic feature of glaucoma, and accordingly, protection of these cells constitutes a major therapeutic objective in the disease. Here, we demonstrate the key influence of caveolin (Cav) in regulating the inner retinal homeostasis in two models of experimentally elevated intraocular pressure (IOP). Two groups of Cav-1-/- and wild-type mice were used in the study. Animals were subjected to experimentally induced chronic and acutely elevated IOP and any changes in their retinal function were assessed by positive scotopic threshold response recordings. TUNEL and cleaved caspase-3 assays were performed to evaluate apoptotic changes in the retina while Brn3a immunostaining was used as a marker to assess and quantify ganglion cell layer (GCL) changes. H&E staining was carried out on retinal sections to evaluate histological differences in retinal laminar structure. Cav-1 ablation partially protected the inner retinal function in both chronic and acute models of elevated IOP. The protective effects of Cav-1 loss were also evident histologically by reduced loss of GCL density in both models. The phenotypic protection in Cav-1-/- glaucoma mice paralleled with increased TrkB phosphorylation and reduced endoplasmic reticulum stress markers and apoptotic activation in the inner retinas. This study corroborated previous findings of enhanced Shp2 phosphorylation in a chronic glaucoma model and established a novel role of Cav-1 in mediating activation of this phosphatase in the inner retina in vivo. Collectively, these findings highlight the critical involvement of Cav-1 regulatory mechanisms in ganglion cells in response to increased IOP, implicating Cav-1 as a potential therapeutic target in glaucoma.
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Affiliation(s)
- Mojdeh Abbasi
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia
| | - Vivek K Gupta
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia.
| | - Nitin Chitranshi
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia.
| | - Veer B Gupta
- School of Medicine, Deakin University, Melbourne, VIC, Australia
| | - Mehdi Mirzaei
- Department of Molecular Science, Macquarie University, North Ryde, NSW, 2109, Australia.,Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, 2109, Australia
| | - Yogita Dheer
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia
| | - Linda Garthwaite
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia
| | - Thiri Zaw
- Department of Molecular Science, Macquarie University, North Ryde, NSW, 2109, Australia
| | - Robert G Parton
- Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland, 4072, Australia.,Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, Australia
| | - Yuyi You
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia.,Save Sight Institute, Sydney University, Sydney, NSW, 2000, Australia
| | - Stuart L Graham
- Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW, 2109, Australia.,Save Sight Institute, Sydney University, Sydney, NSW, 2000, Australia
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Hubert M, Larsson E, Vegesna NVG, Ahnlund M, Johansson AI, Moodie LW, Lundmark R. Lipid accumulation controls the balance between surface connection and scission of caveolae. eLife 2020; 9:55038. [PMID: 32364496 PMCID: PMC7239661 DOI: 10.7554/elife.55038] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/29/2020] [Indexed: 12/12/2022] Open
Abstract
Caveolae are bulb-shaped invaginations of the plasma membrane (PM) that undergo scission and fusion at the cell surface and are enriched in specific lipids. However, the influence of lipid composition on caveolae surface stability is not well described or understood. Accordingly, we inserted specific lipids into the cell PM via membrane fusion and studied their acute effects on caveolae dynamics. We demonstrate that sphingomyelin stabilizes caveolae to the cell surface, whereas cholesterol and glycosphingolipids drive caveolae scission from the PM. Although all three lipids accumulated specifically in caveolae, cholesterol and sphingomyelin were actively sequestered, whereas glycosphingolipids diffused freely. The ATPase EHD2 restricts lipid diffusion and counteracts lipid-induced scission. We propose that specific lipid accumulation in caveolae generates an intrinsically unstable domain prone to scission if not restrained by EHD2 at the caveolae neck. This work provides a mechanistic link between caveolae and their ability to sense the PM lipid composition.
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Affiliation(s)
- Madlen Hubert
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Elin Larsson
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | | | - Maria Ahnlund
- Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Annika I Johansson
- Swedish Metabolomics Centre, Department of Molecular Biology, Umeå University, Umeå, Sweden
| | | | - Richard Lundmark
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
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36
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Hoa Chung L, Qi Y. Lipodystrophy - A Rare Condition with Serious Metabolic Abnormalities. Rare Dis 2020. [DOI: 10.5772/intechopen.88667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Özen S, Akıncı B, Oral EA. Current Diagnosis, Treatment and Clinical Challenges in the Management of Lipodystrophy Syndromes in Children and Young People. J Clin Res Pediatr Endocrinol 2020; 12:17-28. [PMID: 31434462 PMCID: PMC7127888 DOI: 10.4274/jcrpe.galenos.2019.2019.0124] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Lipodystrophy is a heterogeneous group of disorders characterized by lack of body fat in characteristic patterns, which can be genetic or acquired. Lipodystrophy is associated with insulin resistance that can develop in childhood and adolescence, and usually leads to severe metabolic complications. Diabetes mellitus, hypertriglyceridemia, and hepatic steatosis ordinarily develop in these patients, and most girls suffer from menstrual abnormalities. Severe complications develop at a relatively young age, which include episodes of acute pancreatitis, renal failure, cirrhosis, and complex cardiovascular diseases, and all of these are associated with serious morbidity. Treatment of lipodystrophy consists of medical nutritional therapy, exercise, and the use of anti-hyperglycemic and lipid-lowering agents. New treatment modalities, such as metreleptin replacement, promise much in the treatment of metabolic abnormalities secondary to lipodystrophy. Current challenges in the management of lipodystrophy in children and adolescents include, but are not limited to: (1) establishing specialized centers with experience in providing care for lipodystrophy presenting in childhood and adolescence; (2) optimizing algorithms that can provide some guidance for the use of standard and novel therapies to ensure adequate metabolic control and to prevent complications; (3) educating patients and their parents about lipodystrophy management; (4) improving patient adherence to chronic therapies; (5) reducing barriers to access to novel treatments; and (5) improving the quality of life of these patients and their families.
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Affiliation(s)
- Samim Özen
- Ege University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey,* Address for Correspondence: Ege University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey Phone: +90 232 390 12 30 E-mail:
| | - Barış Akıncı
- Dokuz Eylül University Faculty of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, İzmir, Turkey,University of Michigan Medical School, Department of Medicine, and Brehm Center for Diabetes, Division of Metabolism, Endocrinology, and Diabetes, Michigan, USA
| | - Elif A. Oral
- University of Michigan Medical School, Department of Medicine, and Brehm Center for Diabetes, Division of Metabolism, Endocrinology, and Diabetes, Michigan, USA
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Foss-Freitas MC, Akinci B, Luo Y, Stratton A, Oral EA. Diagnostic strategies and clinical management of lipodystrophy. Expert Rev Endocrinol Metab 2020; 15:95-114. [PMID: 32368944 DOI: 10.1080/17446651.2020.1735360] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/24/2020] [Indexed: 12/16/2022]
Abstract
Introduction: Lipodystrophy is a heterogeneous group of rare diseases characterized by various degrees of fat loss which leads to serious morbidity due to metabolic abnormalities associated with insulin resistance and subtype-specific clinical features associated with underlying molecular etiology.Areas covered: This article aims to help physicians address challenges in diagnosing and managing lipodystrophy. We systematically reviewed the literature on PubMed and Google Scholar databases to summarize the current knowledge in lipodystrophy management.Expert opinion: Adipose tissue is a highly active endocrine organ that regulates metabolic homeostasis in the human body through a comprehensive communication network with other organ systems such as the central nervous system, liver, digestive system, and the immune system. The adipose tissue is capable of producing and secreting numerous factors with important endocrine functions such as leptin that regulates energy homeostasis. Recent developments in the field have helped to solve some of the mysteries behind lipodystrophy that allowed us to get a better understanding of adipocyte function and differentiation. From a clinical standpoint, physicians who suspect lipodystrophy should distinguish the disease from several others that may present with similar clinical features. It is also important for physicians to carefully interpret clinical features, laboratory, and imaging results before moving to more sophisticated tests and making decisions about therapy.
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Affiliation(s)
- Maria C Foss-Freitas
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ribeirao Preto Medical School, Sao Paulo University, Ribeirao Preto, Brazil
| | - Baris Akinci
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Yingying Luo
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | | | - Elif A Oral
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
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Bagias C, Xiarchou A, Bargiota A, Tigas S. Familial Partial Lipodystrophy (FPLD): Recent Insights. Diabetes Metab Syndr Obes 2020; 13:1531-1544. [PMID: 32440182 PMCID: PMC7224169 DOI: 10.2147/dmso.s206053] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 03/31/2020] [Indexed: 12/16/2022] Open
Abstract
Lipodystrophies are a heterogeneous group of congenital or acquired disorders, characterized by partial or generalized loss of adipose tissue. Familial partial lipodystrophy (FPLD) presents with genetic and phenotypic variability with insulin resistance, hypertriglyceridemia and hepatic steatosis being the cardinal metabolic features. The severity of the metabolic derangements is in proportion with the degree of lipoatrophy. The underpinning pathogenetic mechanism is the limited capacity of adipose tissue to store lipids leading to lipotoxicity, low-grade inflammation, altered adipokine secretion and ectopic fat tissue accumulation. Advances in molecular genetics have led to the discovery of new genes and improved our knowledge of the regulation of adipose tissue biology. Diagnosis relies predominantly on clinical findings, such as abnormal fat tissue topography and signs of insulin resistance and is confirmed by genetic analysis. In addition to anthropometry and conventional imaging, new techniques such as color-coded imaging of fat depots allow more accurate assessment of the regional fat distribution and differentiation of lipodystrophic syndromes from common metabolic syndrome phenotype. The treatment of patients with lipodystrophy has proven to be challenging. The use of a human leptin analogue, metreleptin, has recently been approved in the management of FPLD with evidence suggesting improved metabolic profile, satiety, reproductive function and self-perception. Preliminary data on the use of glucagon-like peptide 1 receptor agonists (GLP1 Ras) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in cases of FPLD have shown promising results with reduction in total insulin requirements and improvement in glycemic control. Finally, investigational trials for new therapeutic agents in the management of FPLD are underway.
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Affiliation(s)
- Christos Bagias
- Department of Endocrinology, University of Ioannina, Ioannina, Greece
| | - Angeliki Xiarchou
- Department of Endocrinology, University of Ioannina, Ioannina, Greece
| | | | - Stelios Tigas
- Department of Endocrinology, University of Ioannina, Ioannina, Greece
- Correspondence: Stelios Tigas Department of Endocrinology, University of Ioannina, Ioannina45110, GreeceTel +30 2651007800 Email
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Craveiro Sarmento AS, Ferreira LC, Lima JG, de Azevedo Medeiros LB, Barbosa Cunha PT, Agnez-Lima LF, Galvão Ururahy MA, de Melo Campos JTA. The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:30-52. [PMID: 31416577 DOI: 10.1016/j.mrrev.2019.03.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/18/2019] [Accepted: 03/22/2019] [Indexed: 11/26/2022]
Abstract
Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare disease characterized by the near total absence of body fat at birth. BSCL etiology involves genetic variations in four different genes: AGPAT2, BSCL2, CAV1, and CAVIN1. The four different biochemical subtypes of the disease are distinguished depending on which gene is mutated. The diagnosis of lipodystrophy can be based on clinical criteria, but the gold standard remains genetic testing. Since many different mutations have already been correlated with the onset of the disease, the most indicative method is DNA sequencing. However, not all laboratories have the resources to perform sequencing. Thus, less expensive techniques that include narrow gene regions may be applied. In such cases, the target mutations to be tested must be carefully determined taking into account the frequency of the description of the mutations in the literature, the nationality of the patient, as well as their phenotype. This review considers the molecular basis of BSCL, including the manual count of the majority of mutations reported in the literature up to the year 2018. Ninety different genetic mutations in 332 cases were reported at different frequencies. Some mutations were distributed homogeneously and others were specific to geographic regions. Type 2 BSCL was mentioned most often in the literature (50.3% of the cases), followed by Type 1 (38.0%), Type 4 (10.2%), and Type 3 (1.5%). The mutations comprised frameshifts (34.4%), nonsense (26.6%), and missense (21.1%). The c.517dupA in the BSCL2 gene was the most frequent (13.3%), followed by c.589-2A>G in the AGPAT2 gene (11.5%), c.507_511delGTATC in the BSCL2 gene (9.7%), c.317-588del in the AGPAT2 gene (7.3%), and c.202C>T in the AGPAT2 gene (4.5%). This information should prove valuable for analysts in making decisions regarding the best therapeutic targets in a population-specific context, which will benefit patients and enable faster and less expensive treatment.
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Affiliation(s)
- Aquiles Sales Craveiro Sarmento
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Leonardo Capistrano Ferreira
- Instituto de Medicina Tropical, Departamento de Bioquímica, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Josivan Gomes Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Lázaro Batista de Azevedo Medeiros
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | | | - Lucymara Fassarella Agnez-Lima
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Marcela Abbott Galvão Ururahy
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Julliane Tamara Araújo de Melo Campos
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
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Vatier C, Vantyghem MC, Storey C, Jéru I, Christin-Maitre S, Fève B, Lascols O, Beltrand J, Carel JC, Vigouroux C, Bismuth E. Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases. Curr Med Res Opin 2019; 35:543-552. [PMID: 30296183 DOI: 10.1080/03007995.2018.1533459] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes. REVIEW Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males. CONCLUSIONS Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications.
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Affiliation(s)
- Camille Vatier
- a Assistance Publique-Hôpitaux de Paris (AP-HP) , Hôpital Saint-Antoine, Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction , Paris , France
- b Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine , Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN) , Paris , France
| | - Marie-Christine Vantyghem
- c CHU Lille , Endocrinologie, Diabétologie, Métabolisme, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Lille , France
| | - Caroline Storey
- d Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert Debré , Service d'endocrinologie diabétologie pédiatrique, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Paris , France
- e Université Paris Diderot , Sorbonne Paris Cité , Paris , France
| | - Isabelle Jéru
- b Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine , Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN) , Paris , France
- f Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine , Laboratoire Commun de Biologie et Génétique Moléculaires , Paris , France
| | - Sophie Christin-Maitre
- a Assistance Publique-Hôpitaux de Paris (AP-HP) , Hôpital Saint-Antoine, Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction , Paris , France
- g Sorbonne Université , Inserm, Hôpital Trousseau , Paris , France
| | - Bruno Fève
- a Assistance Publique-Hôpitaux de Paris (AP-HP) , Hôpital Saint-Antoine, Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction , Paris , France
- b Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine , Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN) , Paris , France
| | - Olivier Lascols
- b Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine , Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN) , Paris , France
- c CHU Lille , Endocrinologie, Diabétologie, Métabolisme, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Lille , France
| | - Jacques Beltrand
- h Assistance publique-Hôpitaux de Paris, Hôpital Universitaire Necker Enfants Malades, Service d'endocrinologie, gynécologie et diabétologie pédiatrique, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Faculté de médecine , Paris , France
| | - Jean-Claude Carel
- d Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert Debré , Service d'endocrinologie diabétologie pédiatrique, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Paris , France
- e Université Paris Diderot , Sorbonne Paris Cité , Paris , France
| | - Corinne Vigouroux
- a Assistance Publique-Hôpitaux de Paris (AP-HP) , Hôpital Saint-Antoine, Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction , Paris , France
- b Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine , Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN) , Paris , France
- f Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine , Laboratoire Commun de Biologie et Génétique Moléculaires , Paris , France
| | - Elise Bismuth
- d Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert Debré , Service d'endocrinologie diabétologie pédiatrique, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Paris , France
- e Université Paris Diderot , Sorbonne Paris Cité , Paris , France
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Akinci B, Meral R, Oral EA. Phenotypic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities. Curr Diab Rep 2018; 18:143. [PMID: 30406415 DOI: 10.1007/s11892-018-1099-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW This article focuses on recent progress in understanding the genetics of lipodystrophy syndromes, the pathophysiology of severe metabolic abnormalities caused by these syndromes, and causes of severe morbidity and a possible signal of increased mortality associated with lipodystrophy. An updated classification scheme is also presented. RECENT FINDINGS Lipodystrophy encompasses a group of heterogeneous rare diseases characterized by generalized or partial lack of adipose tissue and associated metabolic abnormalities including altered lipid metabolism and insulin resistance. Recent advances in the field have led to the discovery of new genes associated with lipodystrophy and have also improved our understanding of adipose biology, including differentiation, lipid droplet assembly, and metabolism. Several registries have documented the natural history of the disease and the serious comorbidities that patients with lipodystrophy face. There is also evolving evidence for increased mortality rates associated with lipodystrophy. Lipodystrophy syndromes represent a challenging cluster of diseases that lead to severe insulin resistance, a myriad of metabolic abnormalities, and serious morbidity. The understanding of these syndromes is evolving in parallel with the identification of novel disease-causing mechanisms.
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Affiliation(s)
- Baris Akinci
- Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, 1000 Wall Street, Room 5313, Ann Arbor, MI, 48105, USA
- Division of Endocrinology, Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Rasimcan Meral
- Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, 1000 Wall Street, Room 5313, Ann Arbor, MI, 48105, USA
| | - Elif Arioglu Oral
- Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, 1000 Wall Street, Room 5313, Ann Arbor, MI, 48105, USA.
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Abstract
The plasma membrane of eukaryotic cells is not a simple sheet of lipids and proteins but is differentiated into subdomains with crucial functions. Caveolae, small pits in the plasma membrane, are the most abundant surface subdomains of many mammalian cells. The cellular functions of caveolae have long remained obscure, but a new molecular understanding of caveola formation has led to insights into their workings. Caveolae are formed by the coordinated action of a number of lipid-interacting proteins to produce a microdomain with a specific structure and lipid composition. Caveolae can bud from the plasma membrane to form an endocytic vesicle or can flatten into the membrane to help cells withstand mechanical stress. The role of caveolae as mechanoprotective and signal transduction elements is reviewed in the context of disease conditions associated with caveola dysfunction.
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Affiliation(s)
- Robert G. Parton
- Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Queensland 4060, Australia
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Feng D, Amgalan D, Singh R, Wei J, Wen J, Wei TP, McGraw TE, Kitsis RN, Pessin JE. SNAP23 regulates BAX-dependent adipocyte programmed cell death independently of canonical macroautophagy. J Clin Invest 2018; 128:3941-3956. [PMID: 30102258 PMCID: PMC6118598 DOI: 10.1172/jci99217] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 06/26/2018] [Indexed: 01/19/2023] Open
Abstract
The t-SNARE protein SNAP23 conventionally functions as a component of the cellular machinery required for intracellular transport vesicle fusion with target membranes and has been implicated in the regulation of fasting glucose levels, BMI, and type 2 diabetes. Surprisingly, we observed that adipocyte-specific KO of SNAP23 in mice resulted in a temporal development of severe generalized lipodystrophy associated with adipose tissue inflammation, insulin resistance, hyperglycemia, liver steatosis, and early death. This resulted from adipocyte cell death associated with an inhibition of macroautophagy and lysosomal degradation of the proapoptotic regulator BAX, with increased BAX activation. BAX colocalized with LC3-positive autophagic vacuoles and was increased upon treatment with lysosome inhibitors. Moreover, BAX deficiency suppressed the lipodystrophic phenotype in the adipocyte-specific SNAP23-KO mice and prevented cell death. In addition, ATG9 deficiency phenocopied SNAP23 deficiency, whereas ATG7 deficiency had no effect on BAX protein levels, BAX activation, or apoptotic cell death. These data demonstrate a role for SNAP23 in the control of macroautophagy and programmed cell death through an ATG9-dependent, but ATG7-independent, pathway regulating BAX protein levels and BAX activation.
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Affiliation(s)
- Daorong Feng
- Department of Medicine
- Department of Molecular Pharmacology
| | | | - Rajat Singh
- Department of Medicine
- Department of Molecular Pharmacology
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Jianwen Wei
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, and
| | - Jennifer Wen
- Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA
| | | | - Timothy E. McGraw
- Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA
| | - Richard N. Kitsis
- Department of Medicine
- Department of Cell Biology, and
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
- Wilf Family Cardiovascular Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Jeffrey E. Pessin
- Department of Medicine
- Department of Molecular Pharmacology
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
- Wilf Family Cardiovascular Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
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Han X, Chen S, Flynn E, Wu S, Wintner D, Shen Y. Distinct epigenomic patterns are associated with haploinsufficiency and predict risk genes of developmental disorders. Nat Commun 2018; 9:2138. [PMID: 29849042 PMCID: PMC5976622 DOI: 10.1038/s41467-018-04552-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 05/08/2018] [Indexed: 12/21/2022] Open
Abstract
Haploinsufficiency is a major mechanism of genetic risk in developmental disorders. Accurate prediction of haploinsufficient genes is essential for prioritizing and interpreting deleterious variants in genetic studies. Current methods based on mutation intolerance in population data suffer from inadequate power for genes with short transcripts. Here we show haploinsufficiency is strongly associated with epigenomic patterns, and develop a computational method (Episcore) to predict haploinsufficiency leveraging epigenomic data from a broad range of tissue and cell types by machine learning methods. Based on data from recent exome sequencing studies on developmental disorders, Episcore achieves better performance in prioritizing likely-gene-disrupting (LGD) de novo variants than current methods. We further show that Episcore is less-biased by gene size, and complementary to mutation intolerance metrics for prioritizing LGD variants. Our approach enables new applications of epigenomic data and facilitates discovery and interpretation of novel risk variants implicated in developmental disorders. Predicting haploinsufficient genes helps to understand the genetic risk underlying developmental disorders. Here, the authors develop a Random Forest-based method that uses epigenomic data to predict haploinsufficiency, Episcore, which is complementary to methods based on mutation intolerance scores.
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Affiliation(s)
- Xinwei Han
- Department of Systems Biology, Columbia University, New York, NY, 10032, USA.,Department of Pediatrics, Columbia University, New York, NY, 10032, USA.,Constellation Pharmaceuticals, 215 First Street, Cambridge, MA, 02142, USA
| | - Siying Chen
- Department of Systems Biology, Columbia University, New York, NY, 10032, USA.,The Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, NY, 10032, USA
| | - Elise Flynn
- Department of Systems Biology, Columbia University, New York, NY, 10032, USA.,The Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, NY, 10032, USA
| | - Shuang Wu
- Department of Biostatistics, Columbia University, New York, NY, 10032, USA
| | - Dana Wintner
- Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, 14853, USA
| | - Yufeng Shen
- Department of Systems Biology, Columbia University, New York, NY, 10032, USA. .,Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA. .,JP Sulzberger Columbia Genome Center, Columbia University, New York, NY, 10032, USA.
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46
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Xu S, Zhang X, Liu P. Lipid droplet proteins and metabolic diseases. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1968-1983. [DOI: 10.1016/j.bbadis.2017.07.019] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 07/14/2017] [Accepted: 07/19/2017] [Indexed: 12/13/2022]
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Guillín-Amarelle C, Fernández-Pombo A, Sánchez-Iglesias S, Araújo-Vilar D. Lipodystrophic laminopathies: Diagnostic clues. Nucleus 2018; 9:249-260. [PMID: 29557732 PMCID: PMC5973260 DOI: 10.1080/19491034.2018.1454167] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/02/2017] [Accepted: 03/15/2018] [Indexed: 01/19/2023] Open
Abstract
The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies). Those disorders in which adipose tissue is affected are called laminopathic lipodystrophies and include type 2 familial partial lipodystrophy and certain premature aging syndromes. This work summarizes the main clinical features of these syndromes, their associated comorbidities and the clues for the differential diagnosis with other lipodystrophic disorders.
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Affiliation(s)
- Cristina Guillín-Amarelle
- UETeM-Molecular Pathology Group, Department of Medicine, IDIS-CIMUS, University of Santiago de Compostela, Spain
| | - Antía Fernández-Pombo
- UETeM-Molecular Pathology Group, Department of Medicine, IDIS-CIMUS, University of Santiago de Compostela, Spain
| | - Sofía Sánchez-Iglesias
- UETeM-Molecular Pathology Group, Department of Medicine, IDIS-CIMUS, University of Santiago de Compostela, Spain
| | - David Araújo-Vilar
- UETeM-Molecular Pathology Group, Department of Medicine, IDIS-CIMUS, University of Santiago de Compostela, Spain
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Marsboom G, Chen Z, Yuan Y, Zhang Y, Tiruppathi C, Loyd JE, Austin ED, Machado RF, Minshall RD, Rehman J, Malik AB. Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension. Mol Biol Cell 2017; 28:1177-1185. [PMID: 28468941 PMCID: PMC5415014 DOI: 10.1091/mbc.e16-11-0790] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 03/01/2017] [Accepted: 03/02/2017] [Indexed: 01/04/2023] Open
Abstract
A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation.
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Affiliation(s)
- Glenn Marsboom
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612
| | - Zhenlong Chen
- Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612
| | - Yang Yuan
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612
| | - Yanmin Zhang
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.,Department of Pathology, University of Illinois College of Medicine, Chicago, IL 60612
| | - Chinnaswamy Tiruppathi
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612
| | - James E Loyd
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Eric D Austin
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Roberto F Machado
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.,Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612
| | - Richard D Minshall
- Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612
| | - Jalees Rehman
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.,Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612
| | - Asrar B Malik
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612
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Abstract
Over the past decade, interest in caveolae biology has peaked. These small bulb-shaped plasma membrane invaginations of 50-80nm diameter present in most cell types have been upgraded from simple membrane structures to a more complex bona fide organelle. However, although caveolae are involved in several essential cellular functions and pathologies, the underlying molecular mechanisms remain poorly defined. Following the identification of caveolins and cavins as the main caveolae constituents, recent studies have brought new insight into their structural organization as a coat. In this review, we discuss how these new data on caveolae can be integrated in the context of their role in signaling and pathophysiology.
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50
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Abstract
Lipodystrophy disorders are characterized by selective loss of fat tissue with metabolic complications including insulin resistance, hypertriglyceridemia, and nonalcoholic liver disease. These complications can be life-threatening, affect quality of life, and result in increased health care costs. Genetic discoveries have been particularly helpful in understanding the pathophysiology of these diseases, and have shown that mutations affect pathways involved in adipocyte differentiation and survival, lipid droplet formation, and lipid synthesis. In addition, genetic testing can identify patients whose phenotypes are not clearly apparent, but who may still be affected by severe metabolic complications.
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Affiliation(s)
- Marissa Lightbourne
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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