Non-alcoholic fatty liver disease (NAFLD) recently renamed metabolic dysfunction associated steatotic liver disease (MASLD) represents a spectrum of disease states ranging from simple steatosis (a build-up of lipid 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, MASLD 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 transplantation. Despite this, we still do not have any therapeutic options for patients and while weight loss can be effective early, this is not sufficient at the 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 MASLD, 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 MASLD progression. This was the goal of this project. In MyeFattyLiver, we aimed to investigate the different subsets of these cells in both MASLD mouse models and patient liver samples. We wanted to understand which subsets are there and most importantly what each subset does. Using a range of state-of-the-art techniques including single cell and spatial transcriptomics with MyeFattyLiver we have been able to unravel the heterogeneity of myeloid cells in MASLD. We have shown that MASLD results in both the activation and loss of the resident liver macrophages, called Kupffer cells (KCs) and the recruitment of monocytes from the bone marrow which differentiate in the liver towards distinct types of macrophages namely monocyte-derived KCs (moKCs) or lipid associated macrophages (LAMs). Importantly these subsets are highly conserved in human MASLD and we were able to define key conserved gene signatures allowing the different populations to be identified across species and studies. We have also demonstrated a role for efferocytosis of injured/dying cells in driving the LAM phenotype, hinting at how we could generate these cells in vitro. Functionally, we have shown that LAMs and activated KCs (called LAM-like KCs) are critical for tissue repair and preventing fibrosis. This highlights the potential of these cells for future exploitation for therapeutic approaches which could be used to slow and prevent or possibly even reverse MASLD progression.
