Poster 35: LiSyM Midterm Evaluation 2018 Madlen Matz-Soja Junior-Group (Leipzig) Area of Expertise: experimental Methodes: cell isolation, immunohistochemistry, molecular biology, western blotting, Seahorse Scientific Involvement: Junior group LiSyM Resources: 1.000 000 € LiSyM Scientists: [1] PI (Madlen Matz-Soja), [1] PhD Student (Erik Kolbe), [1] Technical Assistant (Doris Mahn) Collaboration: Pillar I; Pillar IV AIM: Contribute to the identification of processes leading to NAFLD and its progression to NASH. Characterization and modelling of the role of Hedgehog signalling (Hh) during the transition from benign steatosis to NAFLD and NASH AIM II A B C D Fig. 1: Postulated aims for the LiSyM project AIM I Fig. 4: Expression of Hh genes and proteins in mice with activated Wnt/ß- Catenin pathway (Apc loxP/loxP) & humans qPCR analysis of A: Gli1, Gli2 and Gli3, B: Ihh, Ptch1,2 and Smo in hepatocytes of Apc wt/wt and Apc loxP/loxP mice (n=8; *, p<0,05; **, p<0,01; ***, p<0,001). Immunofluorescence of C: AXIN2 - green; GS - magenta and merge - white, D: AXIN2 - green; IHH - magenta and merge – white in liver of Apc wt/wt and Apc loxP/loxP mice. AIM III AIM IV Fig.2 Synopsis of all state-dependent Fuzzy-gene regulatory networks. The network shows that the GLI-specific gene knockdown suppresses the expression of the respective Gli gene. GLI2 suppresses the expression of Gli1. Furthermore, Gli2 and Gli3 are coupled by a positive feedback loop. The regulatory activity between GLI1 and GLI3 can be described by either a positive or a negative feedback loop depending on the level of GLI2. Fig. 3 Scatterplot ot the measured and predicted values by the Fuzzy-GRN. The regression lines for GLI1, GLI2, and GLI3 are depicted. The insert shows the parameters of the respective regression line. Fig. 5: Scheme of the altered steroid hormone biosynthesis in female Hh-Ko animals. Red, the significantly increased genes are shown and blue, the lower as an indication of increased androgenization. Fig. 6: IHH as biomarker? Measurement of serum-IHH in human patients with fribrosis. Publications: Matz-Soja M, Computational modelling of Hedgehog signalling in liver regeneration. Drug discovery today – disease models 2017 Rennert C, Eplinius F, Hofmann U, Johänning J, Rolfs F, Schmidt-Heck W, Guthke R, Gebhardt R, Ricken AM, Matz-Soja M. Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility. Arch Toxicol. 2017 Braune J., Weyer U., Matz-Soja M., …, Gebhardt R., and Gericke M. " Hedgehog signaling in macrophages impacts on body weight, adipose tissue inflammation and glucose metabolism." Diabetologia. 2017;60(5):889-899. Urlep Ž., Lorbek G., Perše M., …, Matz-Soja M., and Rozman D. "Ablation of lanosterol 14α-demethylase (Cyp51) expression in hepatocytes defines a male-prevalent hepatic insufficiency in transition to adulthood.” Sci Rep. (2017); 7: 40775. Published online 2017 Matz-Soja M, Rennert C, Schönefeld K, Aleithe S, et al. Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis. Elife. 2016