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) 362 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
Genome Wide Association Studies and clinical studies have identified genetic variants associated with NAFLD progression. However, the function of the associated genes remains to be fully elucidated especially at the cellular level. Here, we propose to take advantage of human Induced Pluriptotent Stems Cells to develop a 3D condition allowing the co-culture of hepatocytes, cholangiocytes, hepatic stellate cells, endothelial cells and macrophages all generated in vitro. This platform will be used to study the mechanisms by which genetic variants can affect interplays between these hepatic cell types and how these modifications can alter hepatocyte resistance to injury induced by fatty acids.
PI: Ludovic Vallier
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 / Joachim Spranger
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
The liver of patients with NAFLD shows a set of alterations in morphometric cellular and tissue parameters, such as increase in the number and size of lipid droplets (LD), defects in hepatocyte polarity and in the three-dimensional (3D) bile canalicular (BC) network. We discovered that apical membrane extensions of hepatocytes, termed apical bulkheads, play a major role in maintaining BC integrity and liver tissue homeostasis. Here, we aim to understand relationship between defects of apical bulkheads and the BC network, LD accumulation and their consequence for NAFLD progression.
PI: Marino Zerial
Macrovesicular steatosis is a well-known risk factor for graft dysfunction after liver transplantation. Normothermic ex vivo liver machine perfusion offers the opportunity of reconditioning liver grafts. We will characterize the molecular and cellular processes during reconditioning of steatotic liver grafts with 2,4-dinitrophenol, decipher the functional role of mitochondrial metabolism for liver defatting, and offer an “organ-in-a-shell” platform for evaluation of new therapeutic strategies for treatment of NAFLD in vivo and ex vivo. Our findings will reveal essential processes in ex vivo reconditioning of steatotic liver grafts.
PI: Nathanael Raschzok / Igor M. Sauer
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
Altered interactions between lipid metabolism and immunity play central roles in NAFLD. We could recently demonstrate that CD1d, an MHC class I-like protein best known for its role in the presentation of lipid antigens to natural killer T (NKT) cells, also contributes to NAFLD progression through NKT cell-in¬de¬pendent effects on hepatic lipid metabolism. Here, we will (i) characterize the cellular origin and mechanisms of NKT cell-independent contributions of CD1d to NAFLD, (ii) investigate the value of therapeutic targeting of CD1d in mice, and (iii) study the role of CD1d in human NAFLD. Together, this will explore CD1d as a central regulator of NAFLD at the intersection of metabolism and inflammation.
PI: Sebastian Zeisig
Hepatocellular senescence develops in response to DNA damage or cellular injury and may determine the course of NAFLD. This project aims to characterise the phenotype and mechanisms of cellular senescence in murine models and humans with NAFLD. State of the art technology will help to decipher the functional heterogeneity of senescent hepatocytes, interactions with immune cells and molecular mechanisms leading to progression to NASH, including mitochondrial dysfunction and cytokine secretion by senescence associated secretory phenotype (SASP). Our findings will provide new therapeutic targets, and senolysis may be applied in various disease stages to halt disease progression.
PI: Cornelius Engelmann / Ingrid Wei Zhang
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