Project Details
Projekt
P7 Employing a systems biology approach to unravel organism-wide and hepatocyte-specific iron-dependent mechanisms regulating BMP signal transduction
Applicant
Professorin Dr. Ursula Klingmüller
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Iron accumulation in the liver is a common precondition associated with chronic liver diseases and has been linked with bone loss. Complex, non-linear interrelations determine the regulation of iron metabolism at multiple scales. In the first funding period, we developed an integrated mathematical model of IL-6 and BMP signal transduction, successfully predicting the dynamics of IL-6 induced hepcidin expression, the main regulator of iron availability, in primary human hepatocytes and HepG2 cells. The model identified that the non-opioid analgesics Diclofenac (DCF) and Acetaminophen (APAP) amplify IL-6 induced hepcidin expression in HepG2 cells by modulating BMP receptor activation. Although many factors like ALK2, ALK3, Hemojuvelin, and Transferrin receptor 2 (TFR2) have been identified as regulators of hepcidin expression, the underlying molecular mechanisms are only partially understood. For example it has been identified that transferrin receptor 1 (TFRC) and TFR2 influence BMP signal transduction by binding BMP ligands and modulating SMAD, AKT, and MAPK pathways. We employed our recently established proteomics pipeline and showed that iron overloading in mice reduces the abundance of TFRC and TFR2 and changes metabolic processes. In the second funding period, we will study the impact of iron changes on the abundance of TFRC/TFR2 and on BMP signal transduction in iron-depleted or overloaded primary murine hepatocytes stimulated with BMP-2 and -6 by quantitative immunoblotting, global mass spectrometry and phosphoproteomics. Since BMP-2 and -6 have different affinities for ALK2 and ALK3, which trigger hepcidin expression to varying degrees, we will explore if co-factors like TFR2, HJV and HFE modulate ligand-receptor interaction in a comparable manner to DCF and APAP. To investigate how this mechanism might be altered in chronic liver disease, we will employ targeted proteomics to study receptor complex composition and BMP-mediated hepcidin expression in human hepatoma cells. Since we observed that the human hepatoma cell line HepG2 secretes BMP ligands, we will determine by antibody-based assays the BMP ligand concentrations in the plasma of mice with liver fibrosis. Chronic liver disease and hepatocellular carcinoma are associated with a significantly increased risk of bone fractures. We aim at testing the hypothesis that (i) alterations in the regulation of iron metabolism are sex-specific, might be (ii) indicative for progression of chronic liver disease and (iii) alter the communication with the bone.
DFG Programme
Research Units
