Unravelling the heterogeneity and functions of hepatic myeloid cells in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease states ranging from simple steatosis (a build-up of fat in the liver) to the more end stage of the disease characterised by fibrosis, cirrhosis and potentially even cancer (termed HCC). Due to the ongoing obesity epidemic, NAFLD has become the disease of the Western world. It is already the biggest cause of HCC in the Western world and by 2030 it is predicted to be the main cause of liver transplants. Despite this, we still do not have any therapeutic options for patients and while weight loss can be effective early in disease, this is not sufficient at the more end stages of the disease spectrum. Immune cells such as macrophages and dendritic cells have been proposed to play crucial roles in driving the progression of NAFLD, but we still do not fully understand what roles they play. This is because in recent years it has become clear that there are many different subsets of these cells in the liver, likely performing different functions. In the past these cells have been studied collectively, however now it's clear that we need to split these up and study them individually to fully understand their unique contributions to NAFLD progression. This is the goal of this project. In MyeFattyLiver, we aim to investigate the different subsets of these cells in both NAFLD models and patient liver samples. We want to understand which subsets are there and most importantly what each subset does. This is crucial because only once we study the individual contributions of these cells can we begin to develop novel therapeutic strategies for patients with NAFLD.

To date we have used state of the art technologies including single cell and spatial transcriptomic approaches to investigate the different subsets of these cells present in the liver in NAFLD models and in patients with NAFLD. Moreover, these technologies allow us to study where in the liver these cells are and with which other cells they interact. This analysis has allowed us to, for the first time, accurately identify the different macrophage and dendritic cell subsets (immune cells) in the healthy and obese human liver. We have identified markers for these different populations so that any lab can now study the different subsets specifically. In addition, we have shown that one population of macrophages present in the healthy liver called Kupffer cells (KCs) are dramatically reduced during NAFLD progression. KCs are lost specifically from regions of the tissue where fat accumulates and fibrosis develops and their loss correlates with disease severity. KCs are then replaced by another population of macrophages called lipid associated macrophages (LAMs) that sense the lipid in the environment which instructs their behaviour. We have identified LAMs both in the models and in the patient samples, suggesting that they may be relevant cells to study further for therapeutic targeting.

Now that we understand the different populations of macrophages and dendritic cells in the NAFLD liver, we are focussing our research efforts on investigating the specific roles for each of these populations. We are doing this by generating models in which we can manipulate these populations one by one and assess how this affects disease progression. By examining the functions of these cells, we hope to be able to determine which cells contribute to or prevent disease progression which will enable us to think about novel therapeutic approaches promoting or restricting these cells and/or their functions to prevent, slow or even reverse the progression of NAFLD

Periodic Reporting for period 2 - MyeFattyLiver (Unravelling the heterogeneity and functions of hepatic myeloid cells in Non-Alcoholic Fatty Liver Disease)

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