Biochemical basis for alcohol-induced liver injury.
Chronic ethanol ingestion leads to hepatocellular injury and alcoholic liver disease (ALD) only if multiple factors combine to favor centrilobular hepatocellular hypoxia. It is hypothesized that these factors include a shift in the redox state, the induction of the microsomal ethanol oxidizing system (MEOS), a high blood alcohol level (BAL), a high polyunsaturated fat diet and episodic decreased O2 supply to the liver. The shift in the redox state favors a low cellular pH, decreased fatty acid oxidation and increased triglyceride formation. The increased MEOS activity increases O2 consumption and portal-central O2 gradient as well as favors acetaldehyde toxic effects including retention of hepatic lipids and export proteins causing cell swelling. The resultant increase in the concentration of acetaldehyde and lactate may stimulate fibrosis as they stimulate collagen synthesis in vitro. The resultant fatty liver narrows the sinusoids slowing sinusoid blood flow. The combination of events reduces available O2 leading to decreased levels of ATP and cellular pH making the liver vulnerable to episodes of systemic hypoxia. The role of membrane changes are reviewed, i.e., 1) membrane fluidity as related to changes in the species of phospholipids, 2) mitochondrial function as related to the changes in the lipid environment of the electron transport chain, and 3) linoleic acid-prostaglandin metabolism. Acute ethanol in vitro has been shown to affect liver cell metabolism regulation by triggering and increasing protein phosphorylation through the Ca2+-phospholipase C pathway. A high fat diet enhances the liver injury caused by chronic ethanol ingestion.
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Department of Pathology, Faculty of Health Sciences, University of Ottawa, Ontario, Canada.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D000431:Ethanol / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats
D004041:Dietary Fats; D000431:Ethanol; D002118:Calcium