Multiple biochemical effects in the pathogenesis of alcoholic fatty liver

Eaton, Simon; Record, C. O.; Bartlett, K.

doi:10.1046/j.1365-2362.1997.1780727.x

Cited by 46 publications

(20 citation statements)

References 40 publications

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“…This might be explained in terms of an activation in PAP. Other authors have in fact described an increase in PAP activity associated with the chronic administration of ethanol [8,28]. Regarding the synthesis of esterified cholesterol from oleate, the results set out in Table 4 show that the levels of radioactivity from oleate in the hepatocytes of rats fed with ethanol were 70% higher than in those of the controls.…”

Section: Resultsmentioning

confidence: 84%

“…Both enzyme reactions generate an excess of reducing equivalents in the liver, mainly in the form of reduced nicotinamide adenine dinucleotide (NADH). If alcohol consumption is chronic, however, the redox change diminishes despite the persistence of fatty liver [3], suggesting that other mechanisms might be involved in the development of steatosis, such as an increase in substrate supply, glycerol 3-phosphate and fatty acids [4,5], an increased phosphatidate phosphohydrolase (PAP) and diacylglycerol acyltransferase activity [6,7,8] and a decrease in the export of triacylglycerols (TAG) [9].…”

Section: Introductionmentioning

confidence: 99%

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Chronic ingestion of ethanol stimulates lipogenic response in rat hepatocytes

2001

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We isolated hepatocytes from rats chronically fed with ethanol and pair-fed control rats and incubated them both in the presence and absence of 100 mM ethanol in order to analyze the uptake into their lipids of several radiolabeled exogenous substrates. The hepatocytes treated chronically with ethanol showed higher lipogenic activity both in neutral lipids and phospholipids from serine, ethanolamine, glycerol and oleate. The only exception found was in the incorporation of choline into phosphatidylcholine (PC), which was lower in the hepatocytes from ethanol-fed rats than in the controls and was concomitant with a decrease in the PC levels of the ethanol-fed hepatocytes. The results obtained after exposing the cells to 100 mM ethanol in vitro indicate that in general the hepatocytes from ethanol-fed rats exhibit a higher lipogenic activity than the control cells. The only difference in the response to ethanol in vitro was found in the biosynthesis of phosphatidylserine (PS) from serine, which rose significantly in control cells but was unaffected in alcoholic hepatocytes. We put this difference in response down to specific adaptation to ethanol feeding.

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Section: Resultsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Chronic ingestion of ethanol stimulates lipogenic response in rat hepatocytes

2001

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“…NAD ϩ / NADH ratio) that results from the metabolism of ethanol and acetaldehyde. Increased levels of NADH will inhibit the NAD ϩ -dependent steps of ␤-oxidation thereby inhibiting fatty acid oxidation (39) and stimulate the activity of various lipogenic enzymes in liver (41). However, ethanol-related alterations in the hepatic redox state have been shown to normalize during continued exposure to ethanol without a concomitant decrease in hepatocyte triglyceride levels (42).…”

Section: Discussionmentioning

confidence: 99%

Modification of the Mitochondrial Proteome in Response to the Stress of Ethanol-dependent Hepatotoxicity

Venkatraman

Landar

Davis

et al. 2004

Journal of Biological Chemistry

162

160

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Mitochondria are particularly susceptible to increased formation of reactive oxygen and nitrogen species in the cell that can occur in response to pathological and xenobiotic stimuli. Proteomics can give insights into both mechanism of pathology and adaptation to stress. Herein we report the use of proteomics to evaluate alterations in the levels of mitochondrial proteins following chronic ethanol exposure in an animal model. Forty-three proteins showed differential expression, 13 increased and 30 decreased, as a consequence of chronic ethanol. Of these proteins, 25 were not previously known to be affected by chronic ethanol emphasizing the power of proteomic approaches in revealing global responses to stress. Both nuclear and mitochondrially encoded gene products of the oxidative phosphorylation complexes in mitochondria from ethanol-fed rats were decreased suggesting an assembly defect in this integrated metabolic pathway. Moreover mtDNA damage was increased by ethanol demonstrating that the effects of ethanol consumption extend beyond the proteome to encompass mtDNA. Taken together, we have demonstrated that chronic ethanol consumption extends to a modification of the mitochondrial proteome far broader than realized previously. These data also suggest that the response of mitochondria to stress may not involve non-discriminate changes in the proteome but is restricted to those metabolic pathways that have a direct role in a specific pathology.Chronic ethanol consumption causes liver damage by a complex process thought to involve oxidative and nitrosative stress, hypoxia, up-regulation of proinflammatory cytokines, and defects in energy metabolism (1-3). As both a source for the formation and target of modifications mediated by reactive oxygen and nitrogen species, the mitochondrion is recognized as a site critical in the cellular stress response induced by chronic ethanol exposure. Increased mitochondrial production of reactive oxygen species (4 -6), oxidation of mitochondrial proteins (7-10), depressed oxidative phosphorylation activity (11-13), and disrupted fatty acid metabolism (14 -16) occur following consumption of alcohol, indicating that ethanol induces significant changes in mitochondria physiology. These responses are also accompanied by a profound increase in the sensitivity of the respiratory chain to inhibition by NO, which we propose plays a key role in contributing to the hypoxia associated with ethanol-dependent hepatotoxicity (17). While mechanisms responsible for ethanol-induced mitochondrial dysfunction have been investigated, the impact of chronic ethanol consumption on the overall content of mitochondrial proteins, the "mitochondrial proteome," has not been studied. Earlier studies by Cunningham and colleagues (18,19) have demonstrated that ethanol consumption decreases the synthesis of the 13 mitochondrially encoded proteins that comprise respiratory complexes I, III, and IV and the ATP synthase. It is proposed that the inhibition of mitochondrial protein synthesis following chronic etha...

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“…Alcohol has been shown to decrease hepatic fatty acid oxidation in vivo and in vitro. Alcohol metabolism alters the intramitochondrial redox potential, which in turn impairs β oxidation and tricarboxylic acid cycle activity (34). In addition, both long-term and short-term alcohol consumption has been shown to suppress the activity of CPT I, a rate-limiting enzyme involved in the transport of long-chain fatty acids into mitochondrial matrix (35,36).…”

Section: Figurementioning

confidence: 99%

The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice

et al. 2003

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Adiponectin has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes. Replenishment of recombinant adiponectin in mice can decrease hyperglycemia, reverse insulin resistance, and cause sustained weight loss without affecting food intake. Here we report its potential roles in alcoholic and nonalcoholic fatty liver diseases in mice. Circulating concentrations of adiponectin decreased significantly following chronic consumption of highfat ethanol-containing food. Delivery of recombinant adiponectin into these mice dramatically alleviated hepatomegaly and steatosis (fatty liver) and also significantly attenuated inflammation and the elevated levels of serum alanine aminotransferase. These therapeutic effects resulted partly from the ability of adiponectin to increase carnitine palmitoyltransferase I activity and enhance hepatic fatty acid oxidation, while it decreased the activities of two key enzymes involved in fatty acid synthesis, including acetyl-CoA carboxylase and fatty acid synthase. Furthermore, adiponectin treatment could suppress the hepatic production of TNF-α and plasma concentrations of this proinflammatory cytokine. Adiponectin was also effective in ameliorating hepatomegaly, steatosis, and alanine aminotransferase abnormality associated with nonalcoholic obese, ob/ob mice. These results demonstrate a novel mechanism of adiponectin action and suggest a potential clinical application of adiponectin and its agonists in the treatment of liver diseases.

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Multiple biochemical effects in the pathogenesis of alcoholic fatty liver

Cited by 46 publications

References 40 publications

Chronic ingestion of ethanol stimulates lipogenic response in rat hepatocytes

Chronic ingestion of ethanol stimulates lipogenic response in rat hepatocytes

Modification of the Mitochondrial Proteome in Response to the Stress of Ethanol-dependent Hepatotoxicity

The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice

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