The role of liver myeloid cells in obesity and metabolic disease

Sammanfattning: Macrophages are tissue resident cells with diverse phenotypes and functions depending on their origin, localization and physiological context. In the liver, their main functions are to detoxify the blood from pathogens, debris and metabolic waste arriving to the liver through the systemic and portal circulation. However, liver macrophages have been shown to change in their composition, phenotype and function during obesity-associated metabolic disease such as nonalcoholic fatty liver disease (NAFLD). NAFLD is a heterogeneous disease and represents a variety of liver conditions ranging from liver steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and cancer. NAFLD has become the major cause of chronic liver disease, since it is associated with an increasing prevalence of obesity and type 2 diabetes. Macrophages contribute to the development of these metabolic disorders in obesity. However, while multiple populations of macrophages have been described in the liver, little is known about their functional role in response to metabolic disease associated with obesity. Herein, we characterized liver macrophages during the development of metabolic disease in mice and humans with obesity. In the first study we used single cell transcriptomics and metabolomics and identified two distinct populations of embryonic-derived tissue resident Kupffer cells (KC1 and KC2) at steady state. While KC1 (CD206lowESAM-) represented the largest population of Kupffer cells, KC2 (CD206highESAM+) cells were characterized by their expression of genes associated with lipid metabolism. Functional characterization of KC2 by either depletion of KC2 cells in the liver or silencing of the fatty acid transporter CD36 in a murine model of obesity and liver steatosis demonstrated that these cells contribute to liver oxidative stress associated with obesity. In the second study we characterized liver samples from lean and obese humans by single cell RNA sequencing and flow cytometry and identified a distinct population of tissue resident myeloid cells, denoted LM2, that expressed high levels of genes regulating oxidative and metabolic stress in obesity, in particular the antioxidant Peroxiredoxin-2. Moreover, functional validation in human primary 2D and 3D in vitro cultures showed that the LM2 cells can reduce oxidative stress induced by lipid accumulation. In summary, these studies have improved our understanding of the composition, diversity and function of liver macrophages in homeostasis and metabolic disease associated with obesity.

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