LAUSR

Background Macrophage uptake of oxidized low-density lipoprotein (oxLDL) which may result in the accumulation of free cholesterol and subsequent crystal formation that can induce NLRP3 inflammasome activation. Hepatic free cholesterol content is significantly increased in human non-alcoholic steatohepatitis. We aim to investigate the roles of free cholesterol and oxLDL deposition on portal venous inflammation, atherosclerosis and fibrosis in the pathogenesis of human non-alcoholic fatty liver disease (NAFLD). Methods Surgical specimens of NAFLD were stained with antibodies against oxLDL, α-smooth muscle actin, lectin-like oxLDL receptor-1 (LOX-1, a scavenger receptor implicated in endothelial dysfunction and atherosclerosis), CD68, CD11b, CD31 and interleukin 1β (IL-1β). Free cholesterol was visualized by filipin stain. The display localization of oxLDL and its associated histopathological changes in serial sections were correlated with other markers. Results Histologically, free cholesterol was co-localized with oxLDL. Their accumulation at the wall of the portal vein is associated with the narrowing of the lumen, plaque formation, endothelium deformation and periportal inflammation. Inflammation was evidenced by the co-localization of Kupffer cells (CD68+ CD11b-) and IL-1β and the expression of LOX-1. Notably, ruptured plaques were closely associated with portal venous inflammation. In cirrhosis, free cholesterol and oxLDL accumulation at periportal and sinusoidal areas were associated with regional stellate cell activation and chicken-wire fibrosis. Conclusions In human NAFLD, free cholesterol and oxLDL accumulation at the portal vein was associated with plaque formation and inflammation, and inflammation was especially prominent in the ruptured plaques. Free cholesterol and oxLDL accumulation in the cirrhotic parenchyma was associated with chicken-wire fibrosis, probably through stellate cell activation. These findings provide not only pathogenic corroboration of atherosclerosis in liver but a direct link between NAFLD and coronary artery disease.