Oxidative Stress-A Key Player in the Course of Alcohol-Related Liver Disease

Abstract

Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.

Keywords: alcohol-related liver disease; micro-RNA; oxidative stress; sirtuin gene family.

Figure 1

Natural history of alcohol-related liver disease. (AFL—alcoholic fatty liver, AH—alcoholic hepatitis, ASH—alcoholic steatohepatitis, ALC—alcohol-related liver cirrhosis, HCC—hepatocellular carcinoma). Chronic alcohol consumption affects healthy liver, leading to the development of AFL in 90–100% of people; 10–35% AFL patients progress to ASH and ALC is the complication in 8–20% of them. Finally, 2% of cirrhotic patients develop HCC. AH is an additional stage of ALD, which might develop from AFL or ASH and directly progresses into ALC (in up to 70% cases).

Figure 2

Oxidative and nitrosative stress in the course of alcohol-related liver disease—main pathways. (SREBP-1c—sterol regulatory element-binding protein 1, PPARα—peroxisome proliferator-activated receptor α, AMPK—AMP-activated protein kinase, Fe—iron, PAMPs—pathogen associated molecular patterns, TLR4—toll-like receptor 4, NF-κB—nuclear factor κ B, DAMPs—danger/damage-associated molecular patterns, SIRT—sirtuin gene family, PRMT1—protein arginine methyltransferase 1, miR—microRNA, mtDNA—mitochondrial DNA).

Figure 3

Alcohol, immune system and crucial cells involved in signaling pathways. Alcohol intake directly influences innate and adaptive immune behaviors, being responsible for the disturbed course of various physiological processes within different type of cells. LPS—lipopolysaccharide, TLR-4—IL—interleukin, TNF-α—tumor necrosis factor alpha, NF-κB—nuclear factor κ B, ROS—reactive oxygen species, MDA—malondialdehyde, 4-HNE—4-hydroxy-2-nonenal—malondialdehyde.