Figure 2.

Harmful effects of acetaldehyde on ALD. Acetaldehyde, one of the oxidative ethanol-derived metabolites, exerts a broad spectrum of damage to the liver, ranging from lipid accumulation in hepatocytes to inflammation, fibrosis, and carcinogenesis. The hepatocytes accumulate lipids by the lipid oversupply (increase of fatty acid (FA) uptake to the liver and de novo lipogenesis in the liver) and/or the impaired pathway of lipid clearance (decrease of mitochondrial β-oxidation and secretion of excessive lipids in very-low density lipoprotein (VLDL)). In addition, acetaldehyde activates Kupffer cells, the liver-resident macrophage, to release reactive oxygen species (ROS) and cytokines that recruit other immune cells. When exposed to acetaldehyde, Kupffer cells activate the toll-like receptor 4 (TLR4)-mediated nuclear factor (NF)-κB signaling pathway, triggering inflammatory responses. The acetaldehyde-protein adducts promote the collagen production by activated hepatic stellate cells (HSCs) via the protein kinase C (PKC) and the TGF-β signaling pathway. ROS-mediated oxidative stress also accelerates liver fibrosis. Moreover, protein and DNA adducts with acetaldehyde cause hepatic carcinogenesis. They weaken DNA integrity and interfere with DNA repair system, increasing carcinogenic DNA mutation. Genetic variations in the alcohol-metabolizing enzymes, such as acetaldehyde dehydrogenase (ALDH)2*2 and alcohol dehydrogenase (ADH)1C*1 alleles, suppress the activity of the enzymes, enhancing the amount of acetaldehyde.