Background & aims: The cause of fatty liver is multifactorial, including genetic and environmental factors. Currently, only a few genetic variants explain the heritability of the disease. QTL analysis of mouse strains enables the identification of genes causing complex human diseases. In a backcross of New Zealand obese (NZO) and C57BL/6J (B6) mice we identified the QTL Ltg/NZO on chromosome 18, which associates with increased liver triglycerides.
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 injection of specific microRNAs in B6 mice. Pulldown coupled with mass-spectrometry-based proteomics and immunoprecipitation were performed to identify interaction partners of IFGGA2.
Results: Through positional cloning, we identified two immunity-related GTPases (Ifgga2, Ifgga4) that prevent hepatic lipid storage. Expression of both murine genes and human orthologue IRGM was significantly lower in fatty livers. Accordingly, liver-specific suppression of either Ifgga2 or Ifgga4 increased hepatic fat content 3 to 4-fold. 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 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 association of LC3B with lipid droplets and decreased triglyceride storage.
Conclusion: IFGGA2 interacts with ATGL and protects from hepatic steatosis presumably by enhancing LC3B binding to lipid droplets.
Keywords: fatty liver; immunity-related GTPases; miRNA; positional cloning.
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Autophagy and Lipid Droplets in the Liver.Annu Rev Nutr. 2015;35:215-37. doi: 10.1146/annurev-nutr-071813-105336. Epub 2015 May 6. Annu Rev Nutr. 2015. PMID: 26076903 Review.
The genetic basis of obesity and type 2 diabetes: lessons from the new zealand obese mouse, a polygenic model of the metabolic syndrome.Results Probl Cell Differ. 2010;52:1-11. doi: 10.1007/978-3-642-14426-4_1. Results Probl Cell Differ. 2010. PMID: 20865367 Review.