Abstract
SummaryMetabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD.
Highlights
Due to the increasing prevalence of obesity and associated insulin resistance, non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic associated fatty liver disease (MAFLD) (Eslam et al, 2020), has become a global problem (Byrne and Targher, 2015)
We have previously reported a similar replacement of the resident KCs (ResKCs) pool by monocyte-derived KCs (moKCs) in mice fed a methionine- and choline-deficient diet (MCD), a protocol that leads to a NASHlike disorder (Devisscher et al, 2017)
Metabolic-associated fatty liver disease (MAFLD) Induces Changes in the Transcriptome and Surface Proteome of Hepatic Immune Cells To assess the roles of hepatic macs in MAFLD, mice were fed a Western diet (WD) consisting of excess fat and cholesterol and supplemented with sucrose and fructose in the drinking water, a protocol generating all stages of human MAFLD and non-alcoholic steatohepatitis (NASH) (Ganz et al, 2015)
Summary
Due to the increasing prevalence of obesity and associated insulin resistance, non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic associated fatty liver disease (MAFLD) (Eslam et al, 2020), has become a global problem (Byrne and Targher, 2015). MAFLD consists of a spectrum of disease states ranging from simple steatosis to the more end-stage of the disease termed non-alcoholic steatohepatitis (NASH), encompassing fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Hepatic macrophages (macs) have been implicated in this process, being activated to become pro-inflammatory by the excess lipids and damage in the fatty liver and by signals originating from the intestine. It is not clear which macs are involved. Kupffer cells (KCs) are the main mac population in the healthy liver, where they reside with at least part of their body in the liver sinusoids, interacting with liver sinusoidal endothelial cells (LSECs), hepatic stellate cells
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