Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation

  1. Schwerbel, Kristin
  2. Kamitz, Anne
  3. Krahmer, Natalie
  4. Hallahan, Nicole
  5. Jähnert, Markus
  6. Gottmann, Pascal
  7. Lebek, Sandra
  8. Schallschmidt, Tanja
  9. Arends, Danny
  10. Schumacher, Fabian
  11. Kleuser, Burkhard
  12. Haltenhof, Tom
  13. Heyd, Florian
  14. Gancheva, Sofiya
  15. Broman, Karl W.
  16. Roden, Michael
  17. Joost, Hans-Georg
  18. Chadt, Alexandra
  19. Al-Hasani, Hadi
  20. Vogel, Heike
  21. Jonas, Wenke
  22. Schürmann, Annette

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WeightNameValue
1000 Titel
  • Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation
1000 Autor/in
  1. Schwerbel, Kristin |
  2. Kamitz, Anne |
  3. Krahmer, Natalie |
  4. Hallahan, Nicole |
  5. Jähnert, Markus |
  6. Gottmann, Pascal |
  7. Lebek, Sandra |
  8. Schallschmidt, Tanja |
  9. Arends, Danny |
  10. Schumacher, Fabian |
  11. Kleuser, Burkhard |
  12. Haltenhof, Tom |
  13. Heyd, Florian |
  14. Gancheva, Sofiya |
  15. Broman, Karl W. |
  16. Roden, Michael |
  17. Joost, Hans-Georg |
  18. Chadt, Alexandra |
  19. Al-Hasani, Hadi |
  20. Vogel, Heike |
  21. Jonas, Wenke |
  22. Schürmann, Annette |
1000 Erscheinungsjahr 2020
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2020-05-04
1000 Erschienen in
1000 Quellenangabe
  • 73(4):771-782
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.jhep.2020.04.031 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957830/ |
1000 Ergänzendes Material
  • https://www.sciencedirect.com/science/article/pii/S0168827820302750#appsec1 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • BACKGROUND & AIMS: Currently, only a few genetic variants explain the heritability of fatty liver disease. Quantitative trait loci (QTL) analysis of mouse strains has identified the susceptibility locus Ltg/NZO (liver triglycerides from New Zealand obese [NZO] alleles) on chromosome 18 as associating with increased hepatic triglycerides. Herein, we aimed to identify genomic variants responsible for this association. METHODS: Recombinant congenic mice carrying 5.3 Mbp of Ltg/NZO were fed a high-fat diet and characterized for liver fat. Bioinformatic analysis, mRNA profiles and electrophoretic mobility shift assays were performed to identify genes responsible for the Ltg/NZO phenotype. Candidate genes were manipulated in vivo by injecting specific microRNAs into C57BL/6 mice. Pulldown coupled with mass spectrometry-based proteomics and immunoprecipitation were performed to identify interaction partners of IFGGA2. RESULTS: Through positional cloning, we identified 2 immunity-related GTPases (Ifgga2, Ifgga4) that prevent hepatic lipid storage. Expression of both murine genes and the human orthologue IRGM was significantly lower in fatty livers. Accordingly, liver-specific suppression of either Ifgga2 or Ifgga4 led to a 3–4-fold greater increase in hepatic fat content. In the liver of low-fat diet-fed mice, IFGGA2 localized to endosomes/lysosomes, while on a high-fat diet it associated with lipid droplets. Pulldown experiments and proteomics identified the lipase ATGL as a binding partner of IFGGA2 which was confirmed by co-immunoprecipitation. Both proteins partially co-localized with the autophagic marker LC3B. Ifgga2 suppression in hepatocytes reduced the amount of LC3B-II, whereas overexpression of Ifgga2 increased the association of LC3B with lipid droplets and decreased triglyceride storage. CONCLUSION: IFGGA2 interacts with ATGL and protects against hepatic steatosis, most likely by enhancing the binding of LC3B to lipid droplets. LAY SUMMARY: The genetic basis of non-alcoholic fatty liver disease remains incompletely defined. Herein, we identified members of the immunity-related GTPase family in mice and humans that act as regulators of hepatic fat accumulation, with links to autophagy. Overexpression of the gene Ifgga2 was shown to reduce hepatic lipid storage and could be a therapeutic target for the treatment of fatty liver disease.
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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1000 Label
1000 Förderer
  1. Bundesministerium für Bildung und Forschung |
  2. State of Brandenburg |
  3. State of North-Rhine-Westfalia |
  4. https://doi.org/10.13039/501100001659 |
1000 Fördernummer
  1. -
  2. -
  3. 82DZD00302; 82DZD00202
  4. KR5166/1-1
1000 Förderprogramm
  1. -
  2. -
  3. -
  4. SFB 958; Emmy-Noether
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Bundesministerium für Bildung und Forschung |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer State of Brandenburg |
    1000 Förderprogramm -
    1000 Fördernummer -
  3. 1000 joinedFunding-child
    1000 Förderer State of North-Rhine-Westfalia |
    1000 Förderprogramm -
    1000 Fördernummer 82DZD00302; 82DZD00202
  4. 1000 joinedFunding-child
    1000 Förderer https://doi.org/10.13039/501100001659 |
    1000 Förderprogramm SFB 958; Emmy-Noether
    1000 Fördernummer KR5166/1-1
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6426752.rdf
1000 Erstellt am 2021-04-13T12:13:07.547+0200
1000 Erstellt von 25
1000 beschreibt frl:6426752
1000 Bearbeitet von 25
1000 Zuletzt bearbeitet 2021-04-13T12:14:35.113+0200
1000 Objekt bearb. Tue Apr 13 12:14:15 CEST 2021
1000 Vgl. frl:6426752
1000 Oai Id
  1. oai:frl.publisso.de:frl:6426752 |
1000 Sichtbarkeit Metadaten public
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