Non-alcoholic fatty liver disease: Translating mechanisms to tailored therapeutic concepts

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, affecting a staggering 25% of the general population. Its prevalence is expected to rise further with an ageing and more obese world population. NAFLD constitutes a major cause of life-threatening sequelae such as liver cirrhosis or hepatocellular carcinoma. While lifestyle interventions have demonstrated some efficacy, no liver-targeted therapy is currently approved. The Transregio-CRC (CRC/TR) on NAFLD will focus on understanding, preventing and treating NAFLD before the development of late stage complications such as decompensated liver cirrhosis or hepatocellular carcinoma. Our consortium seeks to leverage innovative technologies including single-cell and spatial transcriptomics, lipidomics, and organoid modelling, together with outstanding immunological, clinical and translational expertise, to provide yet unprecedented insight into NAFLD-driving cell interactions and pathomechanisms in patients, followed by subsequent functional validation as well as testing of new therapies in experimental models. Taking advantage of these advances, our interdisciplinary research consortium will focus on a bidirectional bedside-to-bench and bench-to-bedside approach defining and targeting mechanisms that drive the transition from a solely metabolic risk to a disease with liver-specific sequelae and grave prognostic relevance. 

Aim

The overarching aim is to gain a holistic understanding of the disease-defining, liver-specific molecular and cellular events in non-alcoholic fatty liver disease.  

Work plan

Projects in two interrelated research areas (A – metabolic injury, B – inflammation and fibrosis) will aim at understanding heterogeneity in mechanisms of hepatocyte metabolic injury, subsequent inflammatory and fibrogenic responses as well as the underlying cell-cell crosstalk in order to develop novel therapeutic concepts. Central projects will provide relevant cross-sectional technologies such as access to extensively phenotyped patient material, transcriptomics, bioinformatics, science data management and an integrated research training group. Together, we will define the events that govern the transition from benign steatosis to non-alcoholic steatohepatitis (NASH) and the involved key players; understand key drivers of hepatic inflammation and fibrogenesis in NAFLD; elucidate the cross-talk between different cell-types and metabolism – inflammation – fibrosis as well as interrelated feed-forward mechanisms in NAFLD; and apply the above concepts to develop novel therapeutic approaches and concepts of multi-modal combination therapy in NAFLD.  

The CRC/TR NAFLD in Berlin and Dresden will open prospects for a new generation of rationally designed and personalized treatment approaches that might prevent the liver of at risk individuals progress from metabolic risk to disease.