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

The sequential pattern of lipid accumulation and associated biochemical changes were studied in two commonly used experimental models of nutritional fatty liver in rats. Female rats were maintained for 8 weeks on high fat, low protein diets containing adequate methionine and choline, and drinking water ad libitum (Diet 1), or deficient in methionine and choline and containing 20% ethanol as a substitute for drinking water (Diet 2). Histologically, there was a progressive increase in liver lipids, mainly in the periportal areas. Occasional foci of liver cell necrosis with lipogranuloma formation occurred in areas of severe fatty change. These changes appeared earlier and were more marked in rats maintained on Diet 2. Electron micrographs revealed large lipid droplets in the liver cells, which sometimes contained myelin figures. The mitochondria were enlarged, distorted and appeared as amorphous structures with disorientated cristae in rats on Diet 1, whereas they had a condensed conformation in rats maintained on Diet 2. Rough endoplasmic reticulum was fragmented and degranulated particularly in rats on Diet 1, and smooth endoplasmic reticulum showed hyperplasia and vesiculation in rats on Diet 2. There was a progressive increase in the total liver lipids and triglycerides in both the groups of rats. This fatty change was accompanied by a significant increase in hepatic 3-hydroxybutyrate, acetoacetate, malate, 2-oxoglutarate, citrate, lactate, ammonia, glutamate, alanine and aspartate, and a significant decrease in oxaloacetate, urea and glucose concentrations. The mass action ratios for alanine aminotransferase, aspartate amino transferase, and glutamate dehydrogenase, generally moved in a parallel direction. Hepatic ATP content was considerably reduced accompanied by a decrease in [ATP]/[ADP] ratios and a significant increased in [lactate]/[pyruvate] and [3-hydroxybutyrate]/[acetoacetate] ratios. There was a corresponding decrease in the [NAD+]/[NADH] ratios both in the cytoplasmic and mitochondrial compartments. These biochemical changes were particularly severe in rats maintained on Diet 1 and Diet 2 for 8 weeks. There was a very good relationship between impaired mitochondrial and endoplasmic reticulum functions, redox and phosphorylation states, and the relevance of their changes to the fate of fatty liver cells.
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PMID:Lipid accumulation in the rat liver: a histological and biochemical study. 23

Palmitylcarnitine oxidation by isolated liver mitochondria has been used to investigate the interaction of fatty acid oxidation with malate, glutamate, succinate, and the malate-aspartate shuttle. Mitochondria preincubated with fluorocitrate were added to a medium containing 2mM ATP and ATPase. This system, characterized by a high energy change, allowed titration of respiration to any desired rate between States 4 and 3 (Chance, B., and Williams, G. R. (1956) Adv. Enzymol. Relat. Areas Mol. Biol. 17, 65-134). When respiration (reference, with palmitylcarnitine and malate as substrates) was set at 75% of State 3, the oxidation of palmitylcarnitine was limited by acetoacetate formation. The addition of malate or glutamate approximately doubled the rate of beta oxidation. Malate circumvented this limitation by citrate formation, but the effect of glutamate apparently was due to enhancement of the capacity for ketogenesis. The rate of beta oxidation was curtailed when malate and glutamate were both present. This curtailment was more pronounced when the malate-aspartate shuttle was fully reconstituted. Among the oxidizable substrates examined, succinate was most effective in inhibiting palmitylcarnitine oxidation. Mitochondrial NADH/NAD+ ratios were correlated positively with suppression of beta oxidation. The degree of suppression of beta oxidation by the malate-aspartate shuttle (NADH oxidation) or by succinate oxidation was dependent on the respiratory state. Both substrates extensively reduced mitochondrial NAD+ and markedly suppressed beta oxidation as respiration approached State 4. Calculations of the rates of flux of hydrogen equivalents through beta oxidation show that the suppression of beta oxidation by glutamate or by the malate-aspartate shuttle is accounted for by increased flux of reducing equivalents through mitochondrial malic dehydrogenase. This increased Flux is accompanied by an increase in the steady state NADH/NAD+ ratio and a marked decrease in the synthesis of citrate. The alpha-glycerophosphate shuttle was reconstituted with mitochondria isolated from rats treated with L-thyroxine. This shuttle was about equal to the reconstructed malate-aspartate shuttle in supression of palmitylcarnitine oxidation. This interaction could not be demonstrated in euthyroid animals owing to the low activity of the mitochondrial alpha-glycerol phosphate dehydrogenase. It is concluded that beta oxidation can be regulated by the NADH/NAD+ ratio. The observed stimulation of flux through malate dehydrogenase both by glutamate and by the malate-aspartate shuttle results in an increased steady state NADH/NAD+ ratio, and is linked to a stoichiometric outward transport of aspartate. We suggest, therefore, that some of the reducing pressure exerted by the malate-aspartate shuttle and by glutamate plus malate is provided through the energy-linked, electrogenic transport of aspartate out of the mitochondria. These results are discussed with respect to the mechanism of the genesis of ethanol-induced fatty liver.
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PMID:Suppression of the mitochondrial oxidation of (-)-palmitylcarnitine by the malate-aspartate and alpha-glycerophosphate shuttles. 124 72

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 metabolic effects of ethanol are due to a direct action of ethanol or its metabolites, changes in the redox state occurring during its metabolism, and modifications of the effects of ethanol by several nutritional factors. Ethanol causes hyperglycemia or hypoglycemia depending whether or not glycogen stores are adequate, inhibits protein synthesis, and results in a fatty liver and elevations in serum triglyceride levels. Increases in serum lactate, results from the increased reduced nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide + (NADH/NAD+) ratio, and hyperuricemia probably occurs owing to the increased turnover of adenine nucleotides after ethanol ingestion. Ethanol decreases thiamine absorption and decreases the enterohepatic circulation of folate. Acetaldehyde, the major metabolite of ethanol, increases the degradation of pyridoxal 5'-phosphate by displacing it from its binding protein and making it susceptible to hydrolysis by membrane-bound alkaline phosphatase. Chronic ethanol administration also results in decreased vitamin A stores and reduced bone mass and blood levels of 25-hydroxyvitamin D. The mechanism whereby ethanol affects these vitamins and their associated enzymes is unknown.
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PMID:The effect of ethanol and its metabolites on carbohydrate, protein, and lipid metabolism. 329 39

The metabolic effects of ethanol are due to a direct action of ethanol or its metabolites, changes in the redox state occurring during its metabolism, and modifications of the effects of ethanol by nutritional factors. Ethanol causes hyperglycemia or hypoglycemia depending on whether glycogen stores are adequate, inhibits protein synthesis, and results in fatty liver and in elevations in serum triglyceride levels. Increases in high-density lipoprotein cholesterol after ethanol ingestion may explain the lower risk of myocardial infarction and death from coronary disease after moderate drinking. Increases in serum lactate, resulting from the increased NADH/NAD+ ratio, and hyperuricemia, most likely the result of increased turnover of adenine nucleotides, are common transient effects of ethanol ingestion. Causes of vitamin deficiencies in alcoholism are decreased dietary intake, decreased intestinal absorption, and alterations in vitamin metabolism. Ethanol decreases thiamine absorption and decreases the enterohepatic circulation of folate. Acetaldehyde increases the degradation of pyridoxal 5'-phosphate by displacing it from its binding protein and making it susceptible to hydrolysis by membrane-bound alkaline phosphatase. Ethanol decreases hepatic vitamin A concentration and its conversion to active retinal, and modifies renal metabolism of vitamin D.
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PMID:Metabolic effects of alcohol. 388 Dec 85

Feeding of ethanol in a liquid diet to male Wistar rats caused decreases in the hepatic cytosolic and mitochondrial [NAD+]/[NADH] ratios. This redox-state change was attenuated after 16 days of feeding ethanol as 36% of the total energy intake. Supplementation of the ethanol-containing liquid diet with Methylene Blue largely prevented the ethanol-induced redox state changes, but did not significantly decrease the severity of the hepatic lipid accumulation that resulted from ethanol ingestion. Methylene Blue did not affect body-weight gain, ethanol intake or serum ethanol concentrations in ethanol-fed rats, nor did the compound influence the hepatic redox state or liver lipid content of appropriate pair-fed control animals. These findings suggest that the altered hepatic redox state that results from ethanol oxidation is not primarily responsible for the production of fatty liver after long-term ethanol feeding in the rat.
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PMID:The effect of methylene blue on the hepatocellular redox state and liver lipid content during chronic ethanol feeding in the rat. 409 27

Early effects of choline deficiency were studied in rats. Nonphospholipid ("neutral lipid") and phospholipid were measured in plasma and in three fractions of a liver homogenate: sediment, supernatant fraction, and "floating fat." A single choline-deficient meal caused significant aberrations from the typical diurnal changes observed in the lipid fractions of the controls. These changes occurred in the following sequence: (a) failure of phospholipid to increase, after feeding, in the sediment fraction; (b) increase of neutral lipid, compared with controls, exclusively in the floating fraction; and (c) failure of neutral lipid to return to control levels. The rate of accumulation of neutral lipid increased during the first 4 days of deficiency. The occurrence of NADH-cytochrome c dehydrogenase in the floating fat and the absence of succinate dehydrogenase activity point to microsomal origin of the floating fat. Early effects of choline deficiency on plasma lipids were limited to phospholipid, and occurred later than changes in the liver. Plasma nonphospholipid levels were unchanged during the first 2 days; this does not support impaired secretion or transportation of glyceride as the cause of fatty liver in the early stages of choline deficiency.
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PMID:Diurnal changes in liver and plasma lipids of choline-deficient rats. 590 Feb 9

Alcoholism is a major health problem, and one of its primary manifestations is alcoholic liver disease. The mechanisms responsible for the various forms of alcoholic liver disease--fatty liver, alcoholic hepatitis, and cirrhosis--are at present poorly understood. Knowledge of these mechanisms is needed to provide a sound framework for the therapy and prevention of liver disease due to alcohol and for the identification of those individuals most susceptible to develop liver disease from alcohol abuse. These experiments were designed specifically to evaluate the postulate that ethanol-induced pericentral liver damage results from an accentuated gradient of decreasing oxygen tension leading to pericentral hypoxia. Microlight guides were used to detect NADH fluorescence, and miniature oxygen electrodes were employed to measure oxygen tensions from periportal and pericentral regions of the liver lobule from the perfused rat liver. With both techniques, ethanol treatment increased the hepatic oxygen gradient. This increase was blocked by the antithyroid drug propylthiouracil. Thus, these experiments provide evidence in support of the hypothesis that pericentral hypoxia is involved in the mechanism of ethanol-induced liver injury. Furthermore, low-flow hypoxia was shown to cause blebs in the pericentral region of the liver lobule in as little as 15 min. This surface blebbing could represent the mechanism for the well-known release of enzymes by impaired hepatic tissues.
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PMID:Alcohol-induced liver injury. The role of oxygen. 637 78

Earlier studies showed that the fatty liver, caused by feeding rats the Lieber-DeCarli alcohol diet for four weeks, was prevented if the diet was supplemented with dihydroxyacetone (22 g/l), pyruvate (22 g/l) and riboflavin (2.2 g/l). In the present study, we observed that fatty liver was prevented if the alcohol diet was supplemented with glycerol and lactate (22 g/l each) and riboflavin (2.2 g/l). Hence, the prevention of alcoholic fatty liver by the dietary supplementation with dihydroxyacetone and pyruvate may not be related to their capacity to serve as hydrogen acceptors and to oxidize NADH produced during ethanol metabolism. When rats were fed the alcohol diet supplemented with either glycerol or pyruvate, the hepatic triglyceride (TG) levels were similar to those in rats pair-fed a Lieber-DeCarli control diet in which alcohol was replaced with an isocaloric amount of dextrins. Therefore, the prevention of fatty liver does not require the simultaneous presence of several supplements. Dietary dihydroxyacetone or riboflavin did not reduce alcoholic fatty liver. Supplementation of the ethanol diet with isocaloric amounts of lactate or glucose, instead of pyruvate, did not abolish the development of fatty liver but caused a marked reduction in the hepatic TG levels. Animals fed the alcohol diet consumed only small amounts of carbohydrate for long periods of time. Since the inclusion of glucose or its metabolites in the alcohol diet fed to rats caused a marked decrease in the liver TG content, it is likely that the production or prevention of fatty liver is related to carbohydrate metabolism.
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PMID:Fatty liver caused by chronic alcohol ingestion is prevented by dietary supplementation with pyruvate or glycerol. 648 82

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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