Chronic ethanol oxygen tension and hepatocyte energy metabolism

Abstract

Hepatocytes from ethanol-fed animals, isolated from either whole liver or the periportal or perivenous regions of the lobule, exhibited an ethanol-related decrease in energy state only when they were oxygen deficient. This was accompanied by an ethanol-related decrease in hepatocyte viability. Both periportal and perivenous hepatocytes from ethanol-fed rats demonstrated increased respiration. The observations reported here are consistent with an ethanol-induced increase in oxygen utilization which could render the perivenous region of the lobule relatively oxygen deficient in the intact liver. This oxygen deficit may cause the decreases in energy state and cell viability associated with chronic ethanol consumption. Ethanol-associated loss in hepatocyte viability appeared to correlate better with a decrease in energy state than with an increase in the products of oxidative stress. An investigation of the association between viability and cellular malondialdehyde levels revealed no effects of chronic ethanol consumption on MDA levels in hepatocytes that demonstrated ethanol-related decreases in cell viability. INTRODUCTIONIt is now well established that chronic ethanol consumption alters those systems involved in oxygen utilization in the liver. With the microsomal system there is an increase in the activity of the mono-oxygenase system which utilizes oxygen to metabolize a variety of organic compounds, including ethanol (1).In contrast, the mitochondrial system, which accounts for about 80% of the hepatocyte's respiratory activity (2), is damaged by chronic ethanol consumption (3,4). Ethanol elicits a decrease in the capacity of the mitochondrion to carry out mitochondrial protein synthesis due to alterations in mitochondrial ribosomes which make them less functional (5). This results in a depression in the translation of the 13 polypeptides encoded by the mitochondrial genome. Since all these proteins are integral components of the oxidative phosphorylation system (6) mitochondrial respiration, measured with isolated mitochondria, is decreased. The net result is a decrease in the rate of ATP synthesis, as has been measured with tightly coupled, isolated mitochondria (3).It has been assumed that the ethanol-elicited depression in the rate of ATP synthesis translates to a decrease in the energy state of the liver, but this relationship has not been rigorously established to date. References to hepatic energy state indicate either the levels of ATP in the tissue, or comparisons of ATP concentrations to those of its breakdown products, ADP and P i , as expressed by the phosphorylation potential (7). The studies described in this paper are investigations of the effects of chronic ethanol consumption on the energy state of hepatic tissue. They were implemented as an initial step in evaluating the relationship between changes in mitochondrial function and liver energetics. It is also important to determine the effects of ethanol on hepatic energy state because the viability of the tissue will depend on the avai...

Effect of Dietary Fat on Chronic Ethanol‐Induced Oxidative Stress in Hepatocytes

“…It correlates much more strongly with a decline in ATP concentrations. These conclusions are supported by our previous observation that lipid peroxide levels can be induced to high levels in hepatocytes from ethanol-fed animals under conditions in which cell viability is maintained (Cunningham and Ivester, 1999).…”

Oxidative stress in alcoholic liver disease: Role of NADPH oxidase complex

“…The mechanisms involved in the condition of steatohepatitis and, consequently, fibrosis could be essentially summarized to three different sites of action. First, hepatocytes determine steatosis in the liver and increase the rate of oxidative stress by several intracellular mechanisms, with the formation of extracellular mediators such as tumor necrosis factor‐alpha (TNF‐α) and cytokines resulting in inflammation 19,20 . Second, is the creation of neo‐antigens able to stimulate the immune response and, consequently, cause leukocyte infiltration in the liver and secretion of cytokines and products of inflammation 36,37 .…”

“…Different cell types in the liver generate reactive oxygen species (ROS) by different mechanisms after chronic alcohol intake 18 . Thus, hepatocytes use mechanisms such as CYP2E1, damage of mitochondrial respiratory burst chain and cytosolic oxidation, 19–21 while Kupffer cells express the phagocytic NADPH oxidase complex as the main mechanism for ROS production 22 . Although hepatocytes and hepatocyte‐specific mechanisms of oxidative stress have historically been the central focus of alcohol‐induced liver injury, several studies have confirmed the role of NADPH oxidase as an important source of ROS in Kupffer cells and hepatic stellate cells that initiate and promote liver injury.…”

Proteomic Analysis Demonstrates Adolescent Vulnerability to Lasting Hippocampal Changes Following Chronic Alcohol Consumption

“…A persistent down-regulation of glycolysis following alcohol intake has broad implications, including a reduced ability for the cell to repair the macromolecular damage that alcohol can create. In hepatocytes harvested from alcohol fed rats, cells remain viable in the presence of oxidative stress only when ATP levels are maintained at near normal levels (Cunningham and Ivester, 1999). It is notable that dysfunction to energy metabolism has been associated with several other neurodegenerative illnesses including Alzheimer's and Huntington's disease, Olivopontocerebellar atrophy, and Wernicke's encephalopathy (Beal, 1992).…”