Hepatic non-parenchymal cells: Master regulators of alcoholic liver disease?

Abstract

Chronic alcohol consumption is one of the most common causes of the progression of alcoholic liver disease (ALD). In the past, alcohol-mediated hepatocyte injury was assumed to be a significantly major cause of ALD. However, a huge number of recent and brilliant studies have demonstrated that hepatic non-parenchymal cells including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells and diverse types of lymphocytes play crucial roles in the pathogenesis of ALD by producing inflammatory mediators such as cytokines, oxidative stress, microRNA, and lipid-originated metabolites (retinoic acid and endocannabinoids) or by directly interacting with parenchymal cells (hepatocytes). Therefore, understanding the comprehensive roles of hepatic non-parenchymal cells during the development of ALD will provide new integrative directions for the treatment of ALD. This review will address the roles of non-parenchymal cells in alcoholic steatosis, inflammation, and liver fibrosis and might help us to discover possible therapeutic targets and treatments involving modulating the non-parenchymal cells in ALD.

Keywords: Alcoholic liver disease; Endocannabinoid; NADPH oxidase; Reactive oxygen stress.

Figure 1

Chronic ethanol consumption increases CYP2E1 expression in hepatocytes and apoptosis of activated hepatic stellate cells. Mice were fed with 5% liquid ethanol (EtOH) or isocaloric control (Pair-fed) diet for 8 wk. A: Liver tissues were stained with antibodies of CYP2E1 and α-smooth muscle actin (α-SMA). Hepatic stellate cells (HSCs) were freshly isolated from pair-fed and ethanol-fed mice; B: Liver tissues were stained with TUNEL and apoptotic bodies of non-parenchymal cells were counted. PT: Portal triad; N: Nucleus of hepatocyte. ^aP < 0.05 in comparison with the corresponding control.

Figure 2

Freshly isolated hepatic stellate cells from liquid ethanol-fed mice were susceptible to natural killer cell killing. A: Mice were fed with 5% liquid ethanol diet for 8 wk. Hepatic stellate cells (HSCs) were freshly isolated from ethanol-fed mice and then co-cultured with natural killer (NK) cells. NK cells were stained with NKG2D antibody and HSCs were stained with RAE1; B: Schematic overview of NKT cell cytotoxicity against activated HSCs via interferon (IFN)-γ-dependent manner.

Figure 3

Model of ethanol-mediated hepatic steatosis and inflammation and preventive effects of toll-like receptor 3 activation in hepatic stellate cells and Kupffer cells against alcoholic liver injury. HSCs: Hepatic stellate cells; EtOH: Ethanol; TLR3: Toll-like receptor 3; IL: Interleukin; LPS: Lipopolysaccharide; TNF-α: Tumor necrosis factor α; NF-κB: Nuclear factor kappa B.