In addition to the disruption of fatty acid synthesis and oxidation, ethanol alters lipid droplet (LD, the storage form of TG) metabolism in hepatocytes and very low-density lipoprotein secretion from the liver. This effect, together with the inhibition of mitochondrial fatty acid β-oxidation, contributes to the pathogenesis of fatty liver (hepatosteatosis), the initial stage of ALD.
Another major pathway of ethanol metabolism that involves CYP2E1, results in the increased production of ROS, highly reactive molecules that interact with and alter lipoprotein lipids, mitochondrial membranes, DNA, and proteins, causing the state known as oxidative stress. Unlike ADH and ALDH, found essentially only in the liver, CYP2E1 is present in other organs, including brain, heart and lungs, thus, consequences of ethanol metabolism via this pathway affect numerous tissues. Ethanol-induced formation of ROS can also be attributable to overproduction of NADH, damage to mitochondria, and activation of Kupffer cells. Additionally, ROS stimulate the release of TNF-α from Kupffer cells, which play an important role in the development of inflammatory reactions and are implicated in tissue damage and formation of fibrosis in the liver. The metabolites formed after alcohol breakdown in the liver can also lead to the formation of ROS. Furthermore, alcohol facilitates production of ROS by reducing the levels of antioxidants, agents that can eliminate ROS (e.g., mitochondrial and cytosolic glutathione, vitamin E).
Acetaldehyde formed as a result of ethanol oxidation and ROS interact with amino acids and other molecules, potentially resulting in the formation of stable and unstable adducts (e.g., malondialdehyde adduct). Formation of protein adducts in hepatocytes impairs protein secretion, which has been proposed to play a role in hepatomegaly. Adduct formation with hemoglobin causes reduced oxygen-binding capacity of red blood cells. Moreover, the formation of acetaldehyde adducts can cause the development of immune response and induce the inflammatory process in hepatocytes. Acetaldehyde is also capable of forming DNA adducts such as 1,N2-propanodeoxyguanosine, which are known to be carcinogenic. Acetaldehyde also forms adducts with neurotransmitters (dopamine) and forms salsolinol, which may contribute to alcohol dependence.
Acetate, another byproduct of ethanol metabolism, increases blood flow into the liver depresses the central nervous system, as well as affects various metabolic processes.
The oxidative phosphorylation of NADH overproduced by ADH and ALDH, require a high input of oxygen. Thus, ethanol metabolism intends to increase oxygen uptake from the blood by hepatocytes in the centrilobular area of the liver lobule, resulting in tissue hypoxia in perivenous regions. The perivenous hepatocytes are the first to show evidence of damage from chronic alcohol consumption. Centrilobular hypoxia can be further enhanced by ethanol- induced changes in liver blood...