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

Schwerbel, K., Kamitz, A., Krahmer, N., Hallahan, N., Jahnert, M., Gottmann, P., et al. (2020). Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. Journal of Hepatology, 73(4), 771-782. doi:10.1016/j.jhep.2020.04.031.

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© 2020 European Association for the Study of the Liver.
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 Creators:
Schwerbel, Kristin1, Author
Kamitz, Anne1, Author
Krahmer, Natalie2, Author           
Hallahan, Nicole1, Author
Jahnert, Markus1, Author
Gottmann, Pascal1, Author
Lebek, Sandra1, Author
Schallschmidt, Tanja1, Author
Arends, Danny1, Author
Schumacher, Fabian1, Author
Kleuser, Burkhard1, Author
Haltenhof, Tom1, Author
Heyd, Florian1, Author
Gancheva, Sofiya1, Author
Broman, Karl W1, Author
Roden, Michael1, Author
Joost, Hans-Georg1, Author
Chadt, Alexandra1, Author
Al-Hasani, Hadi1, Author
Vogel, Heike1, Author
Jonas, Wenke1, AuthorSchurmann, Annette1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: Fatty liver; Immunity-related GTPases; NAFLD; Positional cloning; miRNA
 Abstract: 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 invivo 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. Copyright © 2020 European Association for the Study of the Liver. All rights reserved.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 32376415
DOI: 10.1016/j.jhep.2020.04.031
 Degree: -

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Project name : Emmy-Noether DFG (KR5166/1-1)
Grant ID : -
Funding program : Emmy-Noether
Funding organization : DFG

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Title: Journal of Hepatology
  Other : J. Hepatol.
Source Genre: Journal
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Publ. Info: Amsterdam : Elsevier
Pages: - Volume / Issue: 73 (4) Sequence Number: - Start / End Page: 771 - 782 Identifier: ISSN: 0168-8278
CoNE: https://pure.mpg.de/cone/journals/resource/954925485712