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

Schwerbel, Kristin, Kamitz, Anne, Krahmer, Natalie, Hallahan, Nicole, Jähnert, Markus, Gottmann, Pascal, Lebek, Sandra, Schallschmidt, Tanja, Arends, Danny, Schumacher, Fabian, Kleuser, Burkhard, Haltenhof, Tom, Heyd, Florian, Gancheva, Sofiya, Broman, Karl W., Roden, Michael, Joost, Hans-Georg, Chadt, Alexandra, Al-Hasani, Hadi, Vogel, Heike, Jonas, Wenke and Schürmann, Annette (2020) Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. Journal of Hepatology, 73 (4). pp. 771-782. ISSN 0168-8278

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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.

Item Type: Article
Additional Information: Funding Information: This work was supported by grants from the German Ministry of Education and Research, the State of Brandenburg, and the State of North-Rhine-Westfalia (82DZD00302, AS; 82DZD00202, HA) and by the German Research Foundation (DFG; SFB 958, FH, AS). N.K. is funded by Emmy-Noether DFG (KR5166/1-1).
Uncontrolled Keywords: Fatty liver, Immunity-related GTPases, miRNA, NAFLD, Positional cloning
Subjects: A300 Clinical Medicine
C100 Biology
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 16 Sep 2022 14:19
Last Modified: 16 Sep 2022 14:30

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