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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study possible factors in the pathogenesis of the ethanol-induced fatty liver, we investigated the effect of chronic ethanol consumption on the metabolism of fatty acids by isolated hepatic mitochondria. Chronic ethanol consumption resulted in decreased fatty acid oxidation, as evidenced by a reduction in oxygen uptake and CO2 production associated with the oxidation of fatty acids. The State 3 rate of oxygen uptake was depressed to a greater extent than the State 4 or the uncoupler-stimulated rate; the respiratory control ratio was also decreased. Therefore, one site of action of chronic ethanol feeding is on oxidative phosphorylation. The reduction in fatty acid oxidation, in general, is not due to an effect on the activation or translocation of fatty acids into the mitochondria. There was no effect by ethanol feeding on the activity of palmitoyl coenzyme A synthetase, whereas carnitine palmitoyltransferase activity was increased. The use of an artificial system (formazan production) to study beta oxidation in the absence of the electron transport chain is described. In the presence of fluorocitrate, which inhibits citric acid cycle activity, ketogenesis and formazan production were increased by chronic ethanol consumption. Thus beta oxidation to the level of acetyl-CoA is not impaired by chronic ethanol consumption. Total oxidation of fatty acids to CO2 is depressed by chronic ethanol intoxication because of effects on oxidative phosphorylation or the citric acid cycle (or both). Neither nutritional deficiency, cofactor depletion, nor the presence of ethanol in vitro explains these effects. Several of the effects of chronic ethanol consumption on fatty acid oxidation are mimicked by acetaldehyde and acetate, products of ethanol oxidation. Chronic ethanol consumption leads to persistent impairment of mitochondrial oxidation of fatty acids to CO2. However, oxidation of fatty acids to acetyl-CoA is not decreased by chronic ethanol consumption.
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PMID:Effect of chronic ethanol ingestion on fatty acid oxidation by hepatic mitochondria. 117 Oct 98

The present paper is devoted to overview the basic concepts of ethanol-induced hepatic injury and therapeutic modalities by which alcoholic liver disease can be alleviated. The role of alcohol dehydrogenase of both hepatic and gastric origin as well as the importance of the number one metabolite acetaldehyde are discussed, furthermore the effects of microsomal ethanol oxidizing system are also described. The features of the major clinicopathological consequences of alcohol abuse fatty liver, alcoholic hepatitis are briefly outlined, and the basic pathogenetic mechanisms that lead to cirrhosis--cell necrosis, regeneration and fibroplasia--are shown. The understanding of the pathophysiology of alcohol-induced liver injury may improve the therapy with drugs and nutritional factors, and allow successful prevention through the early recognition of heavy drinkers before their social or medical disintegration. In the management of alcoholic liver diseases, among the true hepatoprotective agents a naturally occurring flavonoid silymarin and an active methyl-donor metabolite S-adenosyl-L-methionine seem to be promising. An antifibrotic treatment with colchicine might also be of importance. Further prospective, well-designed, controlled clinical trials are still warranted to evaluate real efficacy of these drugs. The hepatic consequences of alcohol abuse may be treatable, however, prevention would be the true resolution of the major global health problem of alcoholism.
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PMID:Pathogenesis and management of alcoholic liver injury. 134

Acetaldehyde, a product of ethanol oxidation which forms adducts with proteins, has been incriminated in the pathogenesis of alcoholic liver injury. High serum antibody titers against acetaldehyde-protein adducts have been found not only in alcoholics but also in patients with nonalcoholic liver disease, suggesting a contribution of acetaldehyde derived from sources other than exogenous ethanol. To investigate the effect of liver injury on the removal and the production of acetaldehyde, we produced fibrosis and cirrhosis (by chronic administration of carbon tetrachloride) and fatty liver (with very small doses of dimethylnitrosamine) in rats. Endogenous blood acetaldehyde levels increased by 38% in rats with severe liver injury (p less than 0.005), but not significantly in rats with fatty liver. However, an i.v. load of threonine (a physiological source of acetaldehyde), in amounts equivalent to the daily intake of this amino acid, increased blood and hepatic acetaldehyde levels in the rats with both types of liver injury more than in controls. Threonine dehydrogenase and dehydratase activities, involved in the major pathways for threonine degradation in mitochondria and cytosol, respectively, were markedly decreased in rats with liver injury with a resulting increase in hepatic threonine concentration. Moreover, the threonine aldolase activity, which splits threonine into glycine and acetaldehyde, remained unaffected or even slightly increased. Liver injury was also associated with impaired mitochondrial functions, including a 10 to 23% decrease in acetaldehyde oxidation (depending upon the severity of the lesions). As a consequence, administration of ethanol (an exogenous source of acetaldehyde) resulted in striking elevations in the levels of acetaldehyde in carbon tetrachloride-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High levels of acetaldehyde in nonalcoholic liver injury after threonine or ethanol administration. 251 Nov 35

Chronic ethanol ingestion leads to hepatocellular injury and alcoholic liver disease (ALD) only if multiple factors combine to favor centrilobular hepatocellular hypoxia. It is hypothesized that these factors include a shift in the redox state, the induction of the microsomal ethanol oxidizing system (MEOS), a high blood alcohol level (BAL), a high polyunsaturated fat diet and episodic decreased O2 supply to the liver. The shift in the redox state favors a low cellular pH, decreased fatty acid oxidation and increased triglyceride formation. The increased MEOS activity increases O2 consumption and portal-central O2 gradient as well as favors acetaldehyde toxic effects including retention of hepatic lipids and export proteins causing cell swelling. The resultant increase in the concentration of acetaldehyde and lactate may stimulate fibrosis as they stimulate collagen synthesis in vitro. The resultant fatty liver narrows the sinusoids slowing sinusoid blood flow. The combination of events reduces available O2 leading to decreased levels of ATP and cellular pH making the liver vulnerable to episodes of systemic hypoxia. The role of membrane changes are reviewed, i.e., 1) membrane fluidity as related to changes in the species of phospholipids, 2) mitochondrial function as related to the changes in the lipid environment of the electron transport chain, and 3) linoleic acid-prostaglandin metabolism. Acute ethanol in vitro has been shown to affect liver cell metabolism regulation by triggering and increasing protein phosphorylation through the Ca2+-phospholipase C pathway. A high fat diet enhances the liver injury caused by chronic ethanol ingestion.
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PMID:Biochemical basis for alcohol-induced liver injury. 265 Sep 22

The role of oxygenation in the pathogenesis of alcoholic liver injury was investigated in six baboons fed alcohol chronically and in six pair-fed controls. All animals fed alcohol developed fatty liver with, in addition, fibrosis in three. No evidence for hypoxia was found, both in the basal state and after ethanol at moderate (30 mM) or high (55 mM) levels, as shown by unchanged or even increased hepatic venous partial pressure of O2 and O2 saturation of hemoglobin in the tissue. In controls, ethanol administration resulted in enhanced O2 consumption (offset by a commitant increase in splanchnic blood flow), whereas in alcohol fed animals, there was no increase. At the moderate ethanol dose, the flow-independent O2 extraction, measured by reflectance spectroscopy on the liver surface, tended to increase in control animals only, whereas a significant decrease was observed after the high ethanol dose in the alcohol-treated baboons. This was associated with a marked shift in the mitochondrial redox level in the alcohol-fed (but not in control) baboons, with striking rises in splanchnic output of glutamic dehydrogenase and acetaldehyde, reflecting mitochondrial injury. Increased acetaldehyde, in turn, may aggravate the mitochondrial damage and exacerbate defective O2 utilization. Thus impaired O2 consumption rather than lack of O2 supply characterizes liver injury produced by high ethanol levels in baboons fed alcohol chronically.
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PMID:Impaired oxygen utilization. A new mechanism for the hepatotoxicity of ethanol in sub-human primates. 270 29

The effects of ethanol administration on activity and regulation of carnitine palmitoyltransferase I (CPT-I) were studied in hepatocytes isolated from rats fed a liquid, high-fat diet containing 36% of total calories as ethanol or an isocaloric amount of sucrose. Cells were isolated at several time points in the course of a 5-week experimental period. Ethanol consumption markedly decreased CPT-I activity and increased enzyme sensitivity to inhibition by exogenously added malonyl-CoA. Changes in enzyme activity occurred sooner than those in enzyme sensitivity. Fatty acid oxidation to CO2 and ketone bodies was depressed in hepatocytes from ethanol-fed animals during the first part of the treatment. At the end of the 35-day period, there were no longer differences in the rate of ketogenesis between the two groups. At that time, however, the rate of CO2 formation was still impaired in the ethanol-fed animals. Furthermore, addition of ethanol or acetaldehyde to the incubation medium strongly depressed CPT-I activity and rates of fatty acid oxidation in hepatocytes from ethanol-treated rats, whereas these effects were much less pronounced in cells from control animals. The response of CPT-I activity to insulin, glucagon, vasopressin, and phorbol ester was blunted in cells derived from ethanol-fed rats. These changes in the regulation of CPT-I activity corresponded with those observed in the rate of fatty acid oxidation. It is concluded that CPT-I may play a role in the generation of the ethanol-induced fatty liver.
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PMID:Effects of ethanol feeding on the activity and regulation of hepatic carnitine palmitoyltransferase I. 306 12

The sulphur-containing drug, di-isopropyl-1,3-dithiol-2-ylidenemalonate (Malotilate) protects against the increase in hepatic triglyceride concentration after acute ethanol administration (either 6 g/kg p.o. or 2 g/kg i.p.) in rats. The compound had no influence on the increased hepatic NADH:NAD ratio (measured as the lactate:pyruvate and 3-hydroxybutyrate:acetoacetate ratios) after acute ethanol dosing (2 g/kg i.p.), but was found to lower hepatic acetaldehyde concentrations and prevent some of the disturbances in lipid metabolism observed in liver slices from ethanol-treated animals (e.g. decreased oxidation of [1-14C]palmitate to 14CO2) after this ethanol dose. The drug did not inhibit ethanol metabolism in this acute experiment. Administration of Malotilate to Wistar rats (100 mg/kg/day orally) during chronic feeding of ethanol as 36% of the total calorie intake in a liquid diet, resulted in a lower intake of the alcohol-containing diet by ethanol-fed animals and reduced body weight gain in rats which received the drug, without blood ethanol levels or the ethanol intake (expressed in g/kg body weight/day) being affected. In ethanol-fed animals, Malotilate prevented the production of fatty liver and the adaptive increase in the ethanol elimination rate (EER) normally seen in ethanol-fed animals, although the drug actually caused a slight increase in EER in glucose pair-fed controls. Malotilate did not significantly decrease the degree of induction of microsomal cytochrome P-450 by ethanol, but the increase in aniline hydroxylation was much less marked in animals receiving ethanol and Malotilate, suggesting that the activity of the inducible microsomal ethanol oxidising system (MEOS) may be reduced by the compound. Determination of hepatic acetaldehyde concentrations during ethanol feeding, and during an acute ethanol challenge test following long-term ethanol treatment showed that the compound significantly lowered the level of this ethanol metabolite in the liver under both circumstances. This reduction of hepatic acetaldehyde concentrations, probably resulting in part from the reduced EER as well as increased low-Km aldehyde dehydrogenase activities and glutathione contents seen in the livers of Malotilate-treated rats, are possible mechanisms by which the drug protects against triglyceride accumulation after ethanol administration.
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PMID:The effect of di-isopropyl 1,3 dithiol-2-ylidenemalonate (malotilate) on the hepatic changes induced by ethanol administration in the rat. 314 67

The disulfiram-like reactions following the treatment of cephem antibiotics with methyltetrazolethiol moiety (latamoxef (LMOX) and cefoperazone (CPZ) was studied by using large (500 mg/kg) and small (50 mg/kg) doses of the drugs. Normal and fatty liver rats were injected intraperitoneally with the cephem antibiotics. After overnight fasting blood samples were obtained following an administration of 20% ethanol (2g/kg). Blood ethanol and acetaldehyde concentrations, and liver acetaldehyde dehydrogenase activity were determined. Blood ethanol concentration upon the small dose was similar to that obtained upon the large dose in both groups of normal and fatty liver rats. Blood acetaldehyde concentration upon the large dose was higher than that upon the small dose; 2-fold increase in normal rats and 2.6-4.7-fold increase in fatty liver rats were observed after administering LMOX, while 3.7-fold increase in normal rats and 5-5.7-fold increase in fatty liver rats upon administering CPZ. Additionally, liver acetaldehyde dehydrogenase activity (Enzyme 1) observed upon the large dose was lower than that observed upon the small dose; the degree of reduction was 33% in normal and 19% in fatty liver rats upon the administration of LMOX, while 37% in normal and 45% in fatty liver rats upon the administration of CPZ.
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PMID:[Disulfiram-like reactions resulting from the administration of cephem antibiotics with methyltetrazolethiol moiety examined by using different doses]. 373 64

In alcoholic patients with fatty liver the activity of cytosolic, but not of mitochondrial, acetaldehyde dehydrogenase was lower than in controls. Sequential studies in abstaining alcoholics showed that the cytosolic acetaldehyde dehydrogenase activity remained low, although the previously low activity of alcohol dehydrogenase returned to normal values. It is suggested that reduced cytosolic acetaldehyde dehydrogenase activity may represent a primary defect in alcoholism and is, in part, the cause of the abnormal acetaldehyde metabolism in alcoholic patients. Isoelectric focusing showed distinct isoenzymes of acetaldehyde dehydrogenase in the liver cytosolic and mitochondrial fractions. A survey of eight control subjects and twenty alcoholic patients showed no evidence of a missing or abnormal enzyme in the alcoholic group.
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PMID:Role of hepatic acetaldehyde dehydrogenase in alcoholism: demonstration of persistent reduction of cytosolic activity in abstaining patients. 612 41

Baboons fed ethanol (50% of total calories) chronically develop ultrastructural alterations of hepatic mitochondria. To determine whether mitochondrial functions are also altered, mitochondria were isolated from nine baboons fed ethanol chronically and their pair-fed controls. At the fatty liver stage, ADP-stimulated respiration was depressed in ethanol-fed baboons by 59.4% with glutamate, 43.2% with acetaldehyde, 45.1% with succinate and 51.1% with ascorbate as substrates. A similar decrease was noted in the ADP/O ratio (14 to 28%) and respiratory control ratio (20 to 44%) with all substrates. Similar alterations of mitochondrial functions were observed in baboons with more advanced stages of liver disease, namely fibrosis. These changes after ethanol treatment were associated with decreases in the enzyme activities of mitochondrial respiratory chain: glutamate, NADH and succinate dehydrogenase (42, 24 and 28%, respectively), glutamate-, NADH- or succinate-cytochrome c reductase (42, 27 and 32%, respectively) and cytochrome oxidase (59.6%). The content of all cytochromes was also decreased in ethanol-fed baboons, especially aa3 (57%). Moreover, [14C]leucine incorporation into mitochondrial membranes was depressed by 21% after ethanol treatment. On the other hand, glutamate dehydrogenase activities of serum and cytosol in ethanol-fed baboons were significantly higher than those in pair-fed controls. Morphologically, mitochondria of ethanol-fed baboons were larger than those of pair-fed controls. However, the mitochondrial protein content per mitochondrial DNA was unchanged. From these results, we conclude that, morphologically and functionally, hepatic mitochondria in baboons are altered by chronic ethanol consumption; it is noteworthy that these changes are fully developed already at the fatty liver stage, and that morphological alteration appears to reflect the damage of mitochondrial membranes rather than an adaptive hypertrophy.
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PMID:Biochemical and morphological alterations of baboon hepatic mitochondria after chronic ethanol consumption. 653 46


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