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Abstract
The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases—particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this “inflammatory shift”. Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways.
Highlights
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28.7% of these deaths might be attributable to non-communicable diseases, including cardiovascular disease, certain cancers, neuropsychic disorders, and alcoholic liver disease (ALD) [2,3]
The physiopathology of ALD includes steatosis, steatohepatitis, and fibrosis/cirrhosis, which result from both the toxicity of ethanol metabolism and complex immune reactions [4]
Summary
Due to its particular position, the liver is continuously exposed (through the portal vein) to antigens from food, the intestinal flora, potentially pathogenic microorganisms, and other xenobiotics (Figure 1a). The pathophysiology of alcoholic liver steatosis is closely related to the oxidative metabolism of ethanol; the high resulting levels of NADH and acetaldehyde alter the cell’s redox balance This induces expression of early growth response protein-1, which in turn leads to activation of the transcription factor sterol regulatory element binding protein-1C, which induces the expression of lipogenesis genes, and, on the other hand, to the synthesis isoform, the NADPH-dependent cytochrome P450 reductase, and phospholipids [21]. Chronic alcohol consumption upregulates MEOS activity and CYP 2E1 gene expression, leading to increased rates of alcohol degradation to acetaldehyde via MEOS and high amounts of toxic radicals that partially escape the scavenging properties of ethanol and cause liver injury [21]. This cirrhotic stage is followed by severe complications, including portal hypertension and hepatocellular carcinoma (the second leading cause of liver-related cancer death) [27]
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