Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity
Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (...
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| creator | Kanoh, Hirotaka Nitta, Takahiro Go, Shinji Inamori, Kei‐ichiro Veillon, Lucas Nihei, Wataru Fujii, Mayu Kabayama, Kazuya Shimoyama, Atsushi Fukase, Koichi Ohto, Umeharu Shimizu, Toshiyuki Watanabe, Taku Shindo, Hiroki Aoki, Sorama Sato, Kenichi Nagasaki, Mika Yatomi, Yutaka Komura, Naoko Ando, Hiromune Ishida, Hideharu Kiso, Makoto Natori, Yoshihiro Yoshimura, Yuichi Zonca, Asia Cattaneo, Anna Letizia, Marilena Ciampa, Maria Mauri, Laura Prinetti, Alessandro Sonnino, Sandro Suzuki, Akemi Inokuchi, Jin‐ichi |
| description | Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (LCFA) and very‐long‐chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA‐GM3 increase significantly in metabolic disorders, while LCFA‐GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA‐GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4‐mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA‐GM3 and unsaturated VLCFA‐GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand‐molecular docking analysis supports that VLCFA‐GM3 and LCFA‐GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA‐GM3 is a risk factor for TLR4‐mediated disease progression.
Synopsis
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.
GM3 ganglioside in human serum is composed of a variety of fatty acids including long‐chain (LCFA) and very long‐chain (VLCFA). Serum VLCFA‐GM3 levels increase and LCFA‐GM3 levels decrease in metabolic disorders.
GM3 by itself has no effects on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhanced TLR4 activation by LPS/HMGB1while LCFA‐ and unsaturated VLCFA‐GM3 suppress TLR4 activation.
GM3 interacts with extracellular regions of TLR4/MD2 complex, and modulates dimerization/oligomerization. Ligand‐macromolecular docking study suggested that VLCFA‐ and LCFA‐GM3 act as agonist and antagonist against TLR4 activation, respectively, by differentially binding to hydrophobic pocket of MD2.
VLCFA‐GM3 could be a risk factor for TLR4‐mediated disease progression.
Graphical Abstract
Analysis of GM3 ganglioside composition in human serum under c |
| doi_str_mv | 10.15252/embj.2019101732 |
| format | Article |
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Synopsis
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.
GM3 ganglioside in human serum is composed of a variety of fatty acids including long‐chain (LCFA) and very long‐chain (VLCFA). Serum VLCFA‐GM3 levels increase and LCFA‐GM3 levels decrease in metabolic disorders.
GM3 by itself has no effects on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhanced TLR4 activation by LPS/HMGB1while LCFA‐ and unsaturated VLCFA‐GM3 suppress TLR4 activation.
GM3 interacts with extracellular regions of TLR4/MD2 complex, and modulates dimerization/oligomerization. Ligand‐macromolecular docking study suggested that VLCFA‐ and LCFA‐GM3 act as agonist and antagonist against TLR4 activation, respectively, by differentially binding to hydrophobic pocket of MD2.
VLCFA‐GM3 could be a risk factor for TLR4‐mediated disease progression.
Graphical Abstract
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.15252/embj.2019101732</identifier><identifier>PMID: 32378734</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adipose tissue ; Agonists ; Animals ; Binding ; Cell activation ; chronic inflammation ; Dimerization ; Disease ; EMBO19 ; Fatty acids ; G(M3) Ganglioside - chemistry ; G(M3) Ganglioside - genetics ; G(M3) Ganglioside - metabolism ; ganglioside GM3 ; HEK293 Cells ; HMGB1 protein ; Humans ; Hydrophobicity ; inflammation amplification loop ; Inflammatory diseases ; Insulin ; Ligands ; Lipids ; Lipopolysaccharides ; Macromolecules ; Macrophages ; Metabolic disorders ; Mice ; Mice, Mutant Strains ; Molecular docking ; Monocytes ; Monocytes - chemistry ; Monocytes - metabolism ; Obesity ; Obesity - genetics ; Obesity - metabolism ; Oligomerization ; Pathogenesis ; Protein Multimerization ; Risk analysis ; Risk factors ; Serum levels ; Signal Transduction ; Signaling ; Signs and symptoms ; Species ; TLR4 ; TLR4 protein ; Toll-Like Receptor 4 - chemistry ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - metabolism ; Toll-like receptors</subject><ispartof>The EMBO journal, 2020-06, Vol.39 (12), p.e101732-n/a</ispartof><rights>The Author(s) 2020</rights><rights>2020 The Authors. Published under the terms of the CC BY 4.0 license</rights><rights>2020 The Authors. Published under the terms of the CC BY 4.0 license.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-1148-2688 ; 0000-0002-0703-5746</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298289/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298289/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,41120,42189,45574,45575,46409,46833,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32378734$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanoh, Hirotaka</creatorcontrib><creatorcontrib>Nitta, Takahiro</creatorcontrib><creatorcontrib>Go, Shinji</creatorcontrib><creatorcontrib>Inamori, Kei‐ichiro</creatorcontrib><creatorcontrib>Veillon, Lucas</creatorcontrib><creatorcontrib>Nihei, Wataru</creatorcontrib><creatorcontrib>Fujii, Mayu</creatorcontrib><creatorcontrib>Kabayama, Kazuya</creatorcontrib><creatorcontrib>Shimoyama, Atsushi</creatorcontrib><creatorcontrib>Fukase, Koichi</creatorcontrib><creatorcontrib>Ohto, Umeharu</creatorcontrib><creatorcontrib>Shimizu, Toshiyuki</creatorcontrib><creatorcontrib>Watanabe, Taku</creatorcontrib><creatorcontrib>Shindo, Hiroki</creatorcontrib><creatorcontrib>Aoki, Sorama</creatorcontrib><creatorcontrib>Sato, Kenichi</creatorcontrib><creatorcontrib>Nagasaki, Mika</creatorcontrib><creatorcontrib>Yatomi, Yutaka</creatorcontrib><creatorcontrib>Komura, Naoko</creatorcontrib><creatorcontrib>Ando, Hiromune</creatorcontrib><creatorcontrib>Ishida, Hideharu</creatorcontrib><creatorcontrib>Kiso, Makoto</creatorcontrib><creatorcontrib>Natori, Yoshihiro</creatorcontrib><creatorcontrib>Yoshimura, Yuichi</creatorcontrib><creatorcontrib>Zonca, Asia</creatorcontrib><creatorcontrib>Cattaneo, Anna</creatorcontrib><creatorcontrib>Letizia, Marilena</creatorcontrib><creatorcontrib>Ciampa, Maria</creatorcontrib><creatorcontrib>Mauri, Laura</creatorcontrib><creatorcontrib>Prinetti, Alessandro</creatorcontrib><creatorcontrib>Sonnino, Sandro</creatorcontrib><creatorcontrib>Suzuki, Akemi</creatorcontrib><creatorcontrib>Inokuchi, Jin‐ichi</creatorcontrib><title>Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><description>Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (LCFA) and very‐long‐chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA‐GM3 increase significantly in metabolic disorders, while LCFA‐GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA‐GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4‐mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA‐GM3 and unsaturated VLCFA‐GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand‐molecular docking analysis supports that VLCFA‐GM3 and LCFA‐GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA‐GM3 is a risk factor for TLR4‐mediated disease progression.
Synopsis
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.
GM3 ganglioside in human serum is composed of a variety of fatty acids including long‐chain (LCFA) and very long‐chain (VLCFA). Serum VLCFA‐GM3 levels increase and LCFA‐GM3 levels decrease in metabolic disorders.
GM3 by itself has no effects on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhanced TLR4 activation by LPS/HMGB1while LCFA‐ and unsaturated VLCFA‐GM3 suppress TLR4 activation.
GM3 interacts with extracellular regions of TLR4/MD2 complex, and modulates dimerization/oligomerization. Ligand‐macromolecular docking study suggested that VLCFA‐ and LCFA‐GM3 act as agonist and antagonist against TLR4 activation, respectively, by differentially binding to hydrophobic pocket of MD2.
VLCFA‐GM3 could be a risk factor for TLR4‐mediated disease progression.
Graphical Abstract
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.</description><subject>Adipose tissue</subject><subject>Agonists</subject><subject>Animals</subject><subject>Binding</subject><subject>Cell activation</subject><subject>chronic inflammation</subject><subject>Dimerization</subject><subject>Disease</subject><subject>EMBO19</subject><subject>Fatty acids</subject><subject>G(M3) Ganglioside - chemistry</subject><subject>G(M3) Ganglioside - genetics</subject><subject>G(M3) Ganglioside - metabolism</subject><subject>ganglioside GM3</subject><subject>HEK293 Cells</subject><subject>HMGB1 protein</subject><subject>Humans</subject><subject>Hydrophobicity</subject><subject>inflammation amplification loop</subject><subject>Inflammatory diseases</subject><subject>Insulin</subject><subject>Ligands</subject><subject>Lipids</subject><subject>Lipopolysaccharides</subject><subject>Macromolecules</subject><subject>Macrophages</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Molecular docking</subject><subject>Monocytes</subject><subject>Monocytes - chemistry</subject><subject>Monocytes - metabolism</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Obesity - metabolism</subject><subject>Oligomerization</subject><subject>Pathogenesis</subject><subject>Protein Multimerization</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>Serum levels</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Signs and symptoms</subject><subject>Species</subject><subject>TLR4</subject><subject>TLR4 protein</subject><subject>Toll-Like Receptor 4 - chemistry</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Toll-like receptors</subject><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kd2L1DAUxYMo7uzqu09S8MWXrsm96TQBEXTZD2UWQdbnkKZpN0Oa1KZV5r8366w7KvgUbs7vHE5yCXnB6CmroII3dmi2p0CZZJTVCI_IivE1LYHW1WOyorBmJWdCHpHjlLaU0krU7Ck5QsBa1MhXpLmKg41p1rMzhQ5tMer5NvY25HGK3qYidsXlNRa9Dr13MbnWFkMWzOL1VKTRGpchF4qbzRdeJNcH7V3o725iY5Obd8_Ik077ZJ_fnyfk68X5zdlVufl8-fHs_aYcUUgou042gC0gcIu0WWttagGNoRxBoDQdalZVjUBoaYut1rru1tqgBKyyAnhC3u1zx6UZbGtsmCft1Ti5QU87FbVTfyvB3ao-flc1SAFC5oDX9wFT_LbYNKvBJWO918HGJSlAKQUKIVhGX_2DbuMy5adnijMUPNfimXr5Z6OHKr-_PwNv98AP5-3uQWdU_VqvuluvOqxXnV9_-HQYs53t7Sk7Q2-nQ4v_ReBPS6mpog</recordid><startdate>20200617</startdate><enddate>20200617</enddate><creator>Kanoh, Hirotaka</creator><creator>Nitta, Takahiro</creator><creator>Go, Shinji</creator><creator>Inamori, Kei‐ichiro</creator><creator>Veillon, Lucas</creator><creator>Nihei, Wataru</creator><creator>Fujii, Mayu</creator><creator>Kabayama, Kazuya</creator><creator>Shimoyama, Atsushi</creator><creator>Fukase, Koichi</creator><creator>Ohto, Umeharu</creator><creator>Shimizu, Toshiyuki</creator><creator>Watanabe, Taku</creator><creator>Shindo, Hiroki</creator><creator>Aoki, Sorama</creator><creator>Sato, Kenichi</creator><creator>Nagasaki, Mika</creator><creator>Yatomi, Yutaka</creator><creator>Komura, Naoko</creator><creator>Ando, Hiromune</creator><creator>Ishida, Hideharu</creator><creator>Kiso, Makoto</creator><creator>Natori, Yoshihiro</creator><creator>Yoshimura, Yuichi</creator><creator>Zonca, Asia</creator><creator>Cattaneo, Anna</creator><creator>Letizia, Marilena</creator><creator>Ciampa, Maria</creator><creator>Mauri, Laura</creator><creator>Prinetti, Alessandro</creator><creator>Sonnino, Sandro</creator><creator>Suzuki, Akemi</creator><creator>Inokuchi, Jin‐ichi</creator><general>Nature Publishing Group UK</general><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><scope>C6C</scope><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1148-2688</orcidid><orcidid>https://orcid.org/0000-0002-0703-5746</orcidid></search><sort><creationdate>20200617</creationdate><title>Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity</title><author>Kanoh, Hirotaka ; Nitta, Takahiro ; Go, Shinji ; Inamori, Kei‐ichiro ; Veillon, Lucas ; Nihei, Wataru ; Fujii, Mayu ; Kabayama, Kazuya ; Shimoyama, Atsushi ; Fukase, Koichi ; Ohto, Umeharu ; Shimizu, Toshiyuki ; Watanabe, Taku ; Shindo, Hiroki ; Aoki, Sorama ; Sato, Kenichi ; Nagasaki, Mika ; Yatomi, Yutaka ; Komura, Naoko ; Ando, Hiromune ; Ishida, Hideharu ; Kiso, Makoto ; Natori, Yoshihiro ; Yoshimura, Yuichi ; Zonca, Asia ; Cattaneo, Anna ; Letizia, Marilena ; Ciampa, Maria ; Mauri, Laura ; Prinetti, Alessandro ; Sonnino, Sandro ; Suzuki, Akemi ; Inokuchi, Jin‐ichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p3892-ff9b23d2324e30b6aac782bc0432839cf3a155b832d0d3daaa7f6ac39235a1523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adipose tissue</topic><topic>Agonists</topic><topic>Animals</topic><topic>Binding</topic><topic>Cell activation</topic><topic>chronic inflammation</topic><topic>Dimerization</topic><topic>Disease</topic><topic>EMBO19</topic><topic>Fatty acids</topic><topic>G(M3) Ganglioside - chemistry</topic><topic>G(M3) Ganglioside - genetics</topic><topic>G(M3) Ganglioside - metabolism</topic><topic>ganglioside GM3</topic><topic>HEK293 Cells</topic><topic>HMGB1 protein</topic><topic>Humans</topic><topic>Hydrophobicity</topic><topic>inflammation amplification loop</topic><topic>Inflammatory diseases</topic><topic>Insulin</topic><topic>Ligands</topic><topic>Lipids</topic><topic>Lipopolysaccharides</topic><topic>Macromolecules</topic><topic>Macrophages</topic><topic>Metabolic disorders</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Molecular docking</topic><topic>Monocytes</topic><topic>Monocytes - chemistry</topic><topic>Monocytes - metabolism</topic><topic>Obesity</topic><topic>Obesity - genetics</topic><topic>Obesity - metabolism</topic><topic>Oligomerization</topic><topic>Pathogenesis</topic><topic>Protein Multimerization</topic><topic>Risk analysis</topic><topic>Risk factors</topic><topic>Serum levels</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Signs and symptoms</topic><topic>Species</topic><topic>TLR4</topic><topic>TLR4 protein</topic><topic>Toll-Like Receptor 4 - chemistry</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Toll-like receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kanoh, Hirotaka</creatorcontrib><creatorcontrib>Nitta, Takahiro</creatorcontrib><creatorcontrib>Go, Shinji</creatorcontrib><creatorcontrib>Inamori, Kei‐ichiro</creatorcontrib><creatorcontrib>Veillon, Lucas</creatorcontrib><creatorcontrib>Nihei, Wataru</creatorcontrib><creatorcontrib>Fujii, Mayu</creatorcontrib><creatorcontrib>Kabayama, Kazuya</creatorcontrib><creatorcontrib>Shimoyama, Atsushi</creatorcontrib><creatorcontrib>Fukase, Koichi</creatorcontrib><creatorcontrib>Ohto, Umeharu</creatorcontrib><creatorcontrib>Shimizu, Toshiyuki</creatorcontrib><creatorcontrib>Watanabe, Taku</creatorcontrib><creatorcontrib>Shindo, Hiroki</creatorcontrib><creatorcontrib>Aoki, Sorama</creatorcontrib><creatorcontrib>Sato, Kenichi</creatorcontrib><creatorcontrib>Nagasaki, Mika</creatorcontrib><creatorcontrib>Yatomi, Yutaka</creatorcontrib><creatorcontrib>Komura, Naoko</creatorcontrib><creatorcontrib>Ando, Hiromune</creatorcontrib><creatorcontrib>Ishida, Hideharu</creatorcontrib><creatorcontrib>Kiso, Makoto</creatorcontrib><creatorcontrib>Natori, Yoshihiro</creatorcontrib><creatorcontrib>Yoshimura, Yuichi</creatorcontrib><creatorcontrib>Zonca, Asia</creatorcontrib><creatorcontrib>Cattaneo, Anna</creatorcontrib><creatorcontrib>Letizia, Marilena</creatorcontrib><creatorcontrib>Ciampa, Maria</creatorcontrib><creatorcontrib>Mauri, Laura</creatorcontrib><creatorcontrib>Prinetti, Alessandro</creatorcontrib><creatorcontrib>Sonnino, Sandro</creatorcontrib><creatorcontrib>Suzuki, Akemi</creatorcontrib><creatorcontrib>Inokuchi, Jin‐ichi</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kanoh, Hirotaka</au><au>Nitta, Takahiro</au><au>Go, Shinji</au><au>Inamori, Kei‐ichiro</au><au>Veillon, Lucas</au><au>Nihei, Wataru</au><au>Fujii, Mayu</au><au>Kabayama, Kazuya</au><au>Shimoyama, Atsushi</au><au>Fukase, Koichi</au><au>Ohto, Umeharu</au><au>Shimizu, Toshiyuki</au><au>Watanabe, Taku</au><au>Shindo, Hiroki</au><au>Aoki, Sorama</au><au>Sato, Kenichi</au><au>Nagasaki, Mika</au><au>Yatomi, Yutaka</au><au>Komura, Naoko</au><au>Ando, Hiromune</au><au>Ishida, Hideharu</au><au>Kiso, Makoto</au><au>Natori, Yoshihiro</au><au>Yoshimura, Yuichi</au><au>Zonca, Asia</au><au>Cattaneo, Anna</au><au>Letizia, Marilena</au><au>Ciampa, Maria</au><au>Mauri, Laura</au><au>Prinetti, Alessandro</au><au>Sonnino, Sandro</au><au>Suzuki, Akemi</au><au>Inokuchi, Jin‐ichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity</atitle><jtitle>The EMBO journal</jtitle><stitle>EMBO J</stitle><addtitle>EMBO J</addtitle><date>2020-06-17</date><risdate>2020</risdate><volume>39</volume><issue>12</issue><spage>e101732</spage><epage>n/a</epage><pages>e101732-n/a</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><abstract>Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (LCFA) and very‐long‐chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA‐GM3 increase significantly in metabolic disorders, while LCFA‐GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA‐GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4‐mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA‐GM3 and unsaturated VLCFA‐GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand‐molecular docking analysis supports that VLCFA‐GM3 and LCFA‐GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA‐GM3 is a risk factor for TLR4‐mediated disease progression.
Synopsis
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.
GM3 ganglioside in human serum is composed of a variety of fatty acids including long‐chain (LCFA) and very long‐chain (VLCFA). Serum VLCFA‐GM3 levels increase and LCFA‐GM3 levels decrease in metabolic disorders.
GM3 by itself has no effects on TLR4 activation; however, VLCFA‐GM3 synergistically and selectively enhanced TLR4 activation by LPS/HMGB1while LCFA‐ and unsaturated VLCFA‐GM3 suppress TLR4 activation.
GM3 interacts with extracellular regions of TLR4/MD2 complex, and modulates dimerization/oligomerization. Ligand‐macromolecular docking study suggested that VLCFA‐ and LCFA‐GM3 act as agonist and antagonist against TLR4 activation, respectively, by differentially binding to hydrophobic pocket of MD2.
VLCFA‐GM3 could be a risk factor for TLR4‐mediated disease progression.
Graphical Abstract
Analysis of GM3 ganglioside composition in human serum under chronic inflammation conditions reveals that the fatty acid chain length of GM3 ganglioside impacts the inflammatory activation of macrophages via direct modulation of TLR4 signaling.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32378734</pmid><doi>10.15252/embj.2019101732</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0002-1148-2688</orcidid><orcidid>https://orcid.org/0000-0002-0703-5746</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0261-4189 |
| ispartof | The EMBO journal, 2020-06, Vol.39 (12), p.e101732-n/a |
| issn | 0261-4189 1460-2075 |
| language | eng |
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| subjects | Adipose tissue Agonists Animals Binding Cell activation chronic inflammation Dimerization Disease EMBO19 Fatty acids G(M3) Ganglioside - chemistry G(M3) Ganglioside - genetics G(M3) Ganglioside - metabolism ganglioside GM3 HEK293 Cells HMGB1 protein Humans Hydrophobicity inflammation amplification loop Inflammatory diseases Insulin Ligands Lipids Lipopolysaccharides Macromolecules Macrophages Metabolic disorders Mice Mice, Mutant Strains Molecular docking Monocytes Monocytes - chemistry Monocytes - metabolism Obesity Obesity - genetics Obesity - metabolism Oligomerization Pathogenesis Protein Multimerization Risk analysis Risk factors Serum levels Signal Transduction Signaling Signs and symptoms Species TLR4 TLR4 protein Toll-Like Receptor 4 - chemistry Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - metabolism Toll-like receptors |
| title | Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity |
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