Project Details
Projekt
Linear ubiquitination in the adipose tissue influences stage transitions in hepatic disease
Applicant
Professorin Dr. Nieves Peltzer, Ph.D.
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently occurs in obese individuals, with the crosstalk between gonadal white adipose tissue (GWAT) and the liver being a crucial factor. By introducing mutations in the Linear Ubiquitin chain Assembly Complex (LUBAC), which regulates cell fate decisions, we found that excessive cell death in GWAT promotes MASLD, while NF-κB activation in GWAT provides protective effects against liver damage in response to obesity. Building on these findings, the current project aims to identify how cell death and inflammatory processes control the adipose tissue-liver crosstalk. To this purpose, we plan to characterize the secretome of adipocytes and the associated release mechanisms, identifying specific patterns that correlate with liver disease outcome. This involves three work packages: i) defining the cell death fingerprint in GWAT that drives liver disease, ii) identifying protective NF-κB-associated profiles in GWAT, and iii) correlating these findings with data from obese patients to understand the development of MASLD. To achieve this, we will utilize various methodologies, spanning from ex vivo systems to genetically modified mouse models, with a clear pathway towards clinical translation. Through this approach, we aim to construct a comprehensive atlas of cell death and NF-κB fingerprints in obesity, elucidating the GWAT/liver axis. Close collaboration with key researchers within the dangerhep consortium will enhance the execution of the project, leveraging the shared toolbox like intravital imaging (C01), precision-cut liver slices (P03), omics methods (P07) and human biobanking (P08). This integration into the dangerhep consortium offers a unique opportunity to generate valuable datasets that will benefit the entire initiative. Furthermore, conceptual synergies with projects P02 and P03 (focusing on Caspases and NF-kB signaling in liver disease, respectively), P09 (investigating the "point-of-no-return" in obesity-induced liver damage), and P07 (comparing specific lipid species in liver disease) will amplify the scientific outcomes and pave the way for groundbreaking discoveries. Overall, this proposal offers a robust and comprehensive strategy to tackle critical gaps in our understanding of obesity and liver disease. With a well-structured research plan, cutting-edge methodologies, and collaborative efforts within the dangerhep consortium, this project seeks to enhance clinical applications by identifying circulating and local biomarkers associated with either pathological or protective GWAT-liver crosstalk in obese conditions.
DFG Programme
Research Units
