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

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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.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.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.IFGGA2 interacts with ATGL and protects from hepatic steatosis presumably by enhancing LC3B binding to lipid droplets.


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