The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

Abstract

Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.

Reduction of Cell Proliferation by Acute C2H6O Exposure

“…BCL2-associated X protein (BAX), a member of the pro-apoptotic B-cell lymphoma 2 family proteins, plays a pivotal role in the onset of apoptosis induced by ethanol in splenic T and B lymphocytes [ 63 ]. Acute and chronic alcohol intake may also induce changes in the levels of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), which regulate the immune response [ 64 ]. In ethanol-treated animals, we observed a moderate albeit significant increase of SOD2, consistent with its induction under oxidative stress conditions [ 48 ], and an increment of BAX expression, suggesting activation of the apoptotic signaling pathway [ 65 ].…”

Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma

“…Generation of tissue-damaging reactive oxygen species (ROS) from alcohol oxidation has been identified as an important mechanism in hepatocarcinogenesis [119]. ROS promotes HCC development via damaging cellular macromolecules and forming lipid peroxides [120,121]. It also stimulates the production of cytokines, inflammation, cell proliferation and upregulates angiogenesis [122].…”

The Role of B Cells in Adult and Paediatric Liver Injury

“…Alcohol related liver disease (ArLD) is associated with excessive consumption of alcohol causing hepatocyte damage and major shifts in metabolism leading to the retention of fat known as steatosis ( 86 , 103 , 104 ). Cessation of alcohol consumption at the point of early fibrosis and steatosis can reverse ArLD ( 105 , 106 ).…”

“…The toxic effects of acetaldehyde (the breakdown product of alcohol) cause enhanced lipogenesis resulting in the accumulation of fat molecules in the liver. Continued liver inflammation results in hepatic fibrosis and the formation of scar tissue which disrupts cellular formation ( 104 ).…”

“…Alcohol has the ability to downregulate the expression of tight junction proteins permitting the transposition of bacterial constituents and causing a dysbiosis of gut flora, which may contribute to enhanced inflammation due to the presence of higher quantities of dangerous endotoxins ( 104 ). Altered intestinal permeability and bacterial translocation is often seen in ArLD patients ( 103 , 107 , 108 ).…”