ArticleJournal of hepatology2020
Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation.
Article in Journal of hepatology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 48 citations in OpenAlex.
- Targeting lipophagy in atherosclerosis: Molecular mechanisms, pathogenesis and therapeutic interventions (Review).Molecular medicine reports · 2026Review
- Article
- Structural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism.Nature communications · 2025Article
- Pantothenate kinase 4 controls skeletal muscle substrate metabolism.Nature communications · 2025Article
- IRGM/Irgm1 increases autophagy to inhibit activation of NLRP3 inflammasome in inflammatory injury induced acute liver failure.Cell death discovery · 2024Article
- Identification of four mitochondria-related genes in sepsis based on RNA sequencing technology.BMC immunology · 2024Observational
- Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches.European journal of medical research · 2024Review
- Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives.Molecular cancer · 2024Review
- Autophagy and hepatic lipid metabolism: mechanistic insight and therapeutic potential for MASLD.npj metabolic health and disease · 2024Review
- Tissue-specific mechanisms of fat metabolism that focus on insulin actions.Journal of advanced research · 2023Review
- Serum miR-4488 as a potential biomarker of lean nonalcoholic fatty liver disease.Annals of translational medicine · 2023Article
- Sample multiplexing-based targeted pathway proteomics with real-time analytics reveals the impact of genetic variation on protein expression.Nature communications · 2023Article
- Comparative genomic analyses of multiple backcross mouse populations suggest SGCG as a novel potential obesity-modifier gene.Human molecular genetics · 2022Article
- Alterations of Lipid Profile in Livers with Impaired Lipophagy.International journal of molecular sciences · 2022Article
- Pulmonary embolism and 529 human blood metabolites: genetic correlation and two-sample Mendelian randomization study.BMC genomic data · 2022Article
- Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity.Nature communications · 2022Article
- The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy.iScience · 2022Article
- Genetics Is of the Essence to Face NAFLD.Biomedicines · 2021Review
- Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice.International journal of molecular sciences · 2021Article
- Genetic and epigenetic factors determining NAFLD risk.Molecular metabolism · 2021Review
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22 authors at 6 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsCurrently, 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.
methodsRecombinant 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.
resultsThrough 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.
conclusionIFGGA2 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.
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