Energy Availability and Alcohol-Related Liver Pathology
参考资料：Energy Availability and Alcohol-Related Liver Pathology https://pubs.niaaa.nih.gov/publications/arh27-4/291-299.htm
Carol C. Cunningham, Ph.D., and Cynthia G. Van Horn, Ph.D.
Carol C. Cunningham, Ph.D., is professor of biochemistry, and Cynthia G. Van Horn, Ph.D., is a postdoctoral fellow, both in the Department of Biochemistry at Wake Forest University School of Medicine, Winston–Salem, North Carolina.
The studies from the authors’ laboratory were supported by National Institute on Alcohol Abuse and Alcoholism grants AA–02887 and AA–00279, and by training grant AA–07565 (C.G.V.H.).
Alcohol consumption alters the metabolism of the most common type of cell found in the liver, the hepatocyte. The presence of alcohol in the body causes the liver to use more oxygen—for example, when breaking down the alcohol. Increased oxygen use, in turn, causes oxygen deficits in several key cells, particularly in hepatocytes located near the small hepatic veins. These veins return blood to the heart for re–oxygenation after it has passed through the liver. Hepatocytes surrounding these veins are the first to show signs of liver disease. The damage induced by oxygen deficits may be exacerbated by alcohol–induced deficits in other components that are essential for cell survival. For example, adenosine triphosphate (ATP), the cell’s main source of energy, is generated primarily during the course of two sets of metabolic reactions: glycolysis and the mitochondrial oxidative phosphorylation process. Alcohol consumption may interfere with both of these pathways of ATP production through several mechanisms. An inadequate supply of ATP impairs the cell’s ability to perform critical functions, including the repair of alcohol–induced cell damage, and may therefore contribute to cell death and alcoholic liver disease. Key words: chronic AODE (alcohol and other drug effects); alcoholic liver disorder; oxygen; bioavailability; energy, liver; hepatocyte; ATP (adenosine triphosphate); metabolism; mitochondria; glycolysis; oxidative phosphorylation; pathogenesis
A substantial amount of evidence indicates that alcoholic liver disease develops when alcohol alters the cellular environment of the liver, thereby initiating abnormal interactions among various types of liver cells. According to one prominent hypothesis, alcohol causes changes to the walls of the intestine, which allows a harmful bacterial product called endotoxin to pass into the blood more readily (Tsukamoto and Kaplowitz 1996). As a result, endotoxin levels in the blood and tissues rise. The body responds to this increase in endotoxin by launching a coordinated immune response. For example, high endotoxin levels in the liver cause immune cells residing in the liver (Kupffer cells) to release signaling molecules (i.e., cytokines) as well as other compounds (e.g., prostaglandins) that result in a stepped–up inflammatory response. (For more information on endotoxin and its effects on Kupffer cells, see the article in this issue by Wheeler.) Cytokines and prostaglandins, in turn, increase the metabolic activities of liver cells, especially the hepatocytes, which account for approximately 90 percent of the liver cell mass. When their metabolism increases, the cells require more oxygen and fuel (nutrients) to keep pace with this increased metabolic demand. Oxygen is required for many biochemical reactions in the cell, and the breakdown of nutrients provides the energy needed for these reactions. In addition, the breakdown of alcohol itself, which occurs primarily in the hepatocytes, increases the liver’s need for oxygen, as described in the next section.
Under normal circumstances the blood supplies enough oxygen to the liver, but if hepatocytes use up more oxygen because of the breakdown of alcohol, oxygen deficits (i.e., hypoxia) can develop in some liver areas. Hypoxia, in turn, may impede the liver cells’ ability to produce an energy–rich molecule called adenosine triphosphate (ATP), which is generated during the breakdown of nutrients and supplies energy needed for numerous biochemical reactions. Sufficiently high levels of ATP are essential to the survival of all cells; reduced ATP levels in the liver are one factor contributing to liver cell death and may contribute to development of alcoholic cirrhosis.
This article describes alcohol’s effects on hepatocyte metabolism and oxygen use, reviewing the consequences of alcohol–related hypoxia on ATP levels in the liver and summarizing alcohol’s specific effects on the two main cellular pathways of ATP production.
Effects of Alcohol Consumption on Oxygen Use in the Liver
Alcohol consumption can increase the liver cell’s use of oxygen both indirectly and directly. The indirect pathway is associated with the alcohol–induced activation of immune cells (Kupffer cells) that reside in the liver. When Kupffer cells become activated, they release various signaling and stimulatory molecules, including prostaglandin E2. This molecule can stimulate the metabolic activity of the hepatocytes. This metabolic activity consists of breaking down and synthesizing many essential molecules and cell components, and the chemical reactions involved in these processes frequently involve oxygen molecules (i.e., are oxidation and reduction reactions). (For more information on these reactions, see the sidebar “Oxidation and Reduction Reactions.”) Thus, more active metabolism in the liver increases the need for oxygen. Animal studies have yielded results consistent with this scenario, showing that oxygen use in the liver increases after both acute and chronic alcohol administration (Yuki and Thurman 1980; Arteel et al. 1996; Videla et al. 1973).