Research Area A – Metabolic injury

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. 

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.  

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 362 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. 

We will perform a multidimensional characterization of human liver biopsies using single nuclei RNA and epigenetic technologies and combine them with spatial functional genomic and lipidomic technologies and RNA velocity analysis. Clinically, we will analyze both cross-sectional samples of disease strata from normal controls to NASH fibrosis and paired longitudinal samples of patients before and after bariatric surgery. Our findings will allow an unbiased global assessment of cell compartments and pathways in human NAFLD and help to identify clinically relevant molecular drivers for NAFLD outcome, allowing further in-depth investigation in this CRC/TR. 

PI: Jochen Hampe / Andrej Shevchenko 

We are working on developing and refining artificial intelligence (AI) systems, specifically deep learning algorithms, to better diagnose and predict the progression of Non-alcoholic fatty liver disease (NAFLD), a common liver condition. Our goal is to have these systems learn from detailed images of liver tissue, and predict the changes in molecules that lead to injury and stress in liver cells. In particular, we want to identify specific 'disease-driving regions' in liver tissue and understand how different types of liver cells interact to cause injury. Preliminary work has shown success in using these algorithms to recognize patterns in liver tissue samples that correspond to different stages of liver disease. This research could lead to a better understanding of how NAFLD progresses and potentially inform new treatment strategies. 

PI: Jakob Nikolas Kather / Cornelius Engelmann

NAFLD/NASH is a complex disorder involving persistent hepatocyte injury, fibro-inflammatory feedback loops from immune cells –especially macrophages– and Hepatic Stellate Cells (HSCs), and also perturbations in the liver architecture involving sinusoidal endothelium and cholangiocytes. The intricate crosstalk across all involved lineages in human NAFLD/NASH remains elusive, and comprehensive platforms to recapitulate, probe and manipulate the disease are much needed. Here we propose to overcome these challenges by:

1. Developing a human co-culture system combining key liver cell types involved in NAFLD/NASH.

2. Demonstrating the utility of this platform to model hepatocyte injury in progressive NAFLD.

3. Decipher the molecular and functional effects of genomic variants and modulation on the pro-inflammatory crosstalk in NAFLD/NASH.

PI: Ludovic Vallier / Milad Rezvani

To understand NAFLD pathomechanisms translatable to prevention, we use high-throughput multi-omics systems biology to investigate their shifts under a randomized controlled trial for an isocaloric dietary intervention in NAFLD. In so doing we particularly seek to characterize scope and nature of gut microbiome mediation and modulation of lifestyle risk factors, testing resulting causal hypotheses through microbiome transfer into gnotobiotic mouse models. By exploring the wider scope of cross-systems microbiome, metabolome and phenome correlations, we will further assess likelihood of comorbidity, potential drugability, and sex/gender differentiality of NAFLD risk manifestation.

PI: Sofia Forslund / Knut Mai

The contribution of fat-derived signals to the pathogenesis of NAFLD remains incompletely understood as the complex interplay between adipose tissue, immune system and liver homeostasis is difficult to examine in standard models of NAFLD. By taking advantage of lipodystrophic mice and patients suffering from a complete loss of fat tissue and NAFLD we will address the hypothesis that adipose tissue modulates NAFLD by controlling metabolic injury and hepatic inflammation. In-depth immune cell characterizations metabolic analyses and fat transplantation-models will serve to decipher mechanisms driving NAFLD, allowing to develop new concepts for the treatment of NAFLD.

PI: Britta Siegmund / Carl Weidinger

We aim to gain mechanistic understanding of the impact of metabolic injury to the crosstalk between hepatocytes and neighbouring stromal niche (hepatic stellate cells, HSCs). For that we will first generate co-culture organoid models of hepatocytes and HSCs. Then, we will use these as a discovery tool to understand the cellular, genetic and/or epigenetic or metabolic changes occurring to liver cells and their hepatocyte-stroma interactions upon lipid intracellular accumulation driven by either genetic mutations or by exogenous fat exposure. 

PI: Merixtell Huch

 Chronic nutrient excess can induce hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Elevated lipid accumulation in hepatocytes is a hallmark of inflammation-associated NASH and a result of deregulated fatty acid (FA) homeostasis. NASH-derived pro-inflammatory cytokines include tumor necrosis factor-alpha (TNF-α)2,3, LIGHT, lymphotoxin alpha/beta (LTα, LTβ) and interleukin-17A5 (IL-17A) Upon activation of their respective receptors, these cytokines mainly trigger nuclear factor kappa B (NF-ĸB) signaling, influence hepatocyte metabolism, and promote NASH development and progression. Imbalance of liver transcriptional regulations results in perturbed metabolism and can contribute to NASH development. We have shown that adaptive and innate immune cells can contribute to hepatic metabolic reprogramming through cell-cell interaction and secretion of the above- mentioned cytokines, affecting the metabolic capacity of hepatocytes and NASH development. In the recent past, extensive research has identified potential druggable targets such as ligand-dependent nuclear receptors (NRs) and transcription factors (TFs), e.g. peroxisome proliferator-activated receptors (PPARs). PPARs are nuclear hormone receptors and main regulators of lipid metabolism in hepatocytes that can be activated by direct ligand binding, including FAs. Our preliminary experiments have identified a link between chronic inflammation induced metabolic reprogramming and  PPARα/γ repression. By investigating human/mouse tissue, using organoids, cell lines and in vivo NASH mouse models, and by applying different omic-technologies including single-cell metabolomics, we aim to further elucidate the involvement of the PPAR-and other signaling networks in inflammation-related metabolic reprogramming. Thus, we intend to investigate how chronic necro-inflammation in NASH drives metabolic reprogramming in hepatocytes on a (i) molecular and (ii) cellular level and use this know-how to (iii) counterbalance NASH. 

PI: Mathias Heikenwälder