酗酒导致肝细胞损伤和肝细胞缺氧的机制

Energy Availability and Alcohol-Related Liver Pathology

　

　

 

酒精的摄入改变了肝脏中最丰富的一种细胞——肝细胞的新陈代谢。酒精在体内的存在会导致肝脏消耗更多的氧气——例如，当分解酒精的时候。氧消耗的增加反过来又会导致一些关键细胞缺氧，尤其是位于肝 小静脉附近的肝细胞。这些静脉在血液通过肝脏后会返回到心脏进行再氧合。这些静脉周围的肝细胞是第一个显示出肝病症状的。氧气不足引起的损伤可能会因其他组分的酒精引起的缺陷而加重，而这些因素对细胞存活至关重要。例如，细胞的主要能量来源-三磷酸腺苷(ATP)主要是在两 种代谢反应过程中产生的:糖酵解和线粒体氧化磷酸化过程。酒精的消耗可能会通过多种机制干扰ATP生产的这两种途径。ATP供应不足会 降低细胞执行关键功能的能力，包括修复酒精引起的细胞损伤，因此可能导致细胞死亡和酒精性肝病。

　

 

大量证据表明，酒精改变了肝脏的细胞环境，从而引发了各种类型的肝细胞之间的异常相互作用，从而导致酒精性肝病的发生。根据一个突出的假设，酒精引起肠壁的变化，这使得一种叫做内毒素的有害细菌产物更容易进入血液。结果，血液和组织中的内毒素水平上升。人体通过启动协调免疫反应来应对内毒素的增加。例如，肝脏内高的内毒素水平会导致驻留在肝脏的免疫细胞(Kupffer cells)释放信号分子(例如，细胞因子和其他化合物(如前列腺素)，它们会导致炎症反应加剧。细胞因子和前列腺素反过来增加了肝细胞的代谢活动，尤其是肝细胞，它们约占肝细胞质量的90%。当它们的新陈代谢增加时，细胞需要更多的氧气和燃料(营养)以跟上新陈代谢需求的增长。细胞中许多生化反应都需要氧气，营养物质的分解提供了这些反应所需的能量。此外，酒精本身的分解(主要发生在肝细胞中)增加了肝脏对氧气的需求。

　

　

 

在正常情况下，血液为肝脏提供了足够的氧气，但是如果由于酒精的分解，肝细胞消耗了更多的氧气，就会出现缺氧。在某些肝脏区域会发生缺氧。缺氧反过来又会阻碍肝脏细胞产生富含能量的三磷酸腺苷(ATP)分子的能力，三磷酸腺苷(ATP)是在营养物质分解过程中产生的，为许多生化反应提供能量。足够高水平的ATP对所有细胞的生存至关重要;肝脏中ATP水平的降低是导致肝细胞死亡的一个因素，并可能导致酒精性肝硬化的发展。

　

 

酒精消耗对肝脏供氧的影响

饮酒可以间接和直接增加肝细胞的耗氧量。间接途径与存在于肝脏的酒精诱导的免疫细胞(Kupffer细胞)活化有关。当Kupffer细胞被激活时，它们会释放各种信号和刺激分子，包括前列腺素E2。这种分子可以刺激肝细胞的代谢活动。这种代谢活动包括分解和合成许多基本的分子和细胞成分，而这些过程中涉及的化学反应通常涉及到氧分子(即分子氧)，即氧化还原反应。

　

https://s.click.taobao.com/ZnJiNMw

https://s.click.taobao.com/GoLiNMw

　

 

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).

 

 

https://pubs.niaaa.nih.gov/publications/arh27-4/291-299.htm