Molecular Mechanisms of Alcohol-Induced Hepatic Fibrosis

Abstract

Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Before alcoholic liver fibrosis becomes evident, the liver undergoes several stages of alcoholic liver disease including steatosis and steatohepatitis. Although the main mechanisms of fibrogenesis are independent of the etiology of liver injury, alcoholic liver fibrosis is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of cell-toxic and profibrogenic ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Although to date removal of the causative agent, i.e. alcohol, still represents the most effective intervention to prevent the manifestation of alcoholic liver disease, sophisticated molecular approaches are underway, aiming to specifically blunt profibrogenic signaling pathways in liver cells or specifically induce cell death in activated hepatic stellate cells to decrease the scarring of the liver.

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

“…A lack of supplying blood vessels can compromise oxygen and nutrient delivery to tissue undergoing repair (31,32). Hypoxia has been shown to increase the production of collagen as well as profibrogenic factors like plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1, and connective tissue growth factor through an HIF-mediated transcriptional response (33)(34)(35).…”

Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver Fibrosis

“…Because TGF-β1 was implicated in suppression of NK cell activity 33 and HSCs are an important producer of TGF-β1 during HSC activation, 14,15 we investigated whether TGF-β1 was involved in the resistance to NK cell killing of ethanol HSCs. The RT-PCR analyses showed that expression of TGF-β1 mRNA was much stronger in ethanol HSCs than in pair HSCs ( Figure 7B), suggesting that ethanol HSCs produce more TGF-β1.…”

“…11,12 In addition to simply enhancing liver injury, alcohol may accelerate progression of liver fibrosis through several mechanisms. [13][14][15] For instance, alcohol consumption may enhance hepatic HSC activation through an increase in gut-derived endotoxins, hypoxia (oxidative stress), or the formation of toxic and profibrogenic metabolites (eg, acetaldehyde or lipid peroxides). [13][14][15] Recently, we and others have shown that activation of the innate immune system, natural killer (NK) cells and interferon-γ (IFN-γ), inhibits liver fibrosis.…”

“…[13][14][15] For instance, alcohol consumption may enhance hepatic HSC activation through an increase in gut-derived endotoxins, hypoxia (oxidative stress), or the formation of toxic and profibrogenic metabolites (eg, acetaldehyde or lipid peroxides). [13][14][15] Recently, we and others have shown that activation of the innate immune system, natural killer (NK) cells and interferon-γ (IFN-γ), inhibits liver fibrosis. [16][17][18] Moreover, the immunosuppressive effects of ethanol are well documented in alcoholics.…”

Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling

“…This event can be recapitulated in a culture model in which isolated HSCs are cultured on plastic in serumcontaining media. The activated HSCs are a rich source of type I and III fibrillar collagen and also secrete high levels of the tissue inhibitor of metalloproteinase 1 (TIMP-1) [3]. Many of the morphological and metabolic changes associated with HSC activation during fibrogenesis in vivo are also observed in HSCs grown in culture on plastic.…”