Functions of hepatic non-parenchymal cells in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) represents a wide spectrum of disease from simple steatosis to cirrhosis. Although there have been multiple attempts to treat ALD, its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases. However, nearly 40% of patients with ALD who are in need of treatment are unresponsive to the current treatments, which implies a new paradigm shift for the treatment of ALD. Traditionally, earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD. However, increasing evidence suggests that non-parenchymal cells, such as hepatic stellate cells (HSCs), Kupffer cells, liver sinusoidal endothelial cells, and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions. For instance, in the early stage of ALD, Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines (immunologic pathways) and the activation of the endocannabinoid system (metabolic pathways). While the stage of ALD progresses to alcoholic hepatitis and fibrosis, various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level. This review explains the diverse roles of non-parenchymal cells in the progression of ALD, as well as potential therapeutic strategies to treat ALD.