The role of scavenger receptor MARCO in hepatic fibrosis and non-alcoholic steatohepatitis 3513

Abstract Description Obesity is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress to steatohepatitis (MASH) and fibrosis. We explored how macrophage remodeling influences this progression, focusing on the role of the macrophage receptor with collagenous structure (MARCO) therein. Wild-type and Marco-/- mice were fed a normal or choline-deficient high-fat diet (CDHFD) for 15 weeks. Kupffer cells (KC) were analyzed by flow cytometry, fibrosis, and steatosis were assessed histologically. RNA sequencing along with non-targeted metabolomics were performed on liver tissue. High fibrosis after CDHFD was linked to the replacement of resident KC by monocyte-derived macrophages. RNA sequencing showed increased immune responses and decreased metabolic activity, with mitochondrial function negatively and lipid-laden KC positively correlating with fibrosis. MARCO was upregulated on KC during CDHFD feeding. Obese Marco-/- mice exhibited altered KC inflammation, bile acid metabolism, reduced KC lipid content, and increased steatosis, but lower liver injury and fibrosis than controls. Notably, MARCO expression in KC of obese patients positively correlated with insulin resistance and liver injury. These results suggest that macrophage remodeling and reduced mitochondrial fatty acid metabolism perpetuate fibrosis. They further indicate that MARCO-expressing KC influence the balance between steatosis and fibrosis by modulating KC lipid profiles and inflammation. Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)