Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Peroxisomes play a role in hepatic beta-oxidation of fat, a process that results in the production of hydrogen peroxide. The fatty infiltration of the liver that occurs in severely malnourished children remains unexplained. We observed an almost total absence of peroxisomes in the hepatocytes of these children. We suggest that lack of available peroxisomes could contribute to the development of fatty liver.
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PMID:Peroxisomes and the fatty liver of malnutrition: an hypothesis. 848 Jun 89

In this study, the author intended to examine the validity of the inhaled hydrogen gas clearance method (i-H2) for determination of the hepatic blood flow (HBF), and also to show some applicabilities of the method in experimental animals and patients with liver diseases. Simultaneous determinations of HBF by i-H2 and electromagnetic flowmetry in rabbits revealed an excellent correlation between the values obtained by the two methods. Moreover, HBF in rabbits measured by i-H2 varied in parallel with that by thermocouple flowmetry or laser Doppler velocimetry after administration of norepinephrine, propranolol or glucagon. In carbon tetrachloride-treated rats, HBF measured by i-H2 correlated better with the severity of damage in the sinusoidal structure than the severity of hepatic cell injury or the serum levels of transaminases. HBF as determined by i-H2 was significantly decreased in acute hepatitis (AH), chronic inactive hepatitis (CIH), chronic active hepatitis (CAH), liver cirrhosis (LC) and fatty liver. Reduced HBF in AH returned to normal during recovery of the disease. The ratio of HBF in tumor/normal tissue was greater than 1.0 for hepatocellular carcinoma in contrast to the ratio of less than 1.0 for metastatic liver carcinoma. Propranolol caused a decrease in HBF by 31%, and vasopressin by 39% in patients with CIH or LC. In contrast, glucagon induced its increase by 65%, 35% and 17%, respectively, in patients with CIH, AH and LC.
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PMID:[Measurement of hepatic blood flow by the hydrogen gas clearance method. Experimental and clinical observations]. 236 96

Chemical shift is the phenomenon that is seen when an isotope possessing a nuclear magnetic dipole moment resonates at a spectrum of resonance frequencies in a given magnetic field. These resonance frequencies, or chemical shifts, depend on the chemical environments of particular nuclei. Mapping the spatial distribution of nuclei associated with a particular chemical shift (e.g., hydrogen nuclei associated with water molecules or with lipid groups) is called chemical shift imaging. Several techniques of proton chemical shift imaging that have been applied in vivo are presented, and their clinical findings are reported and summarized. Acquiring high-resolution spectra for large numbers of volume elements in two or three dimensions may be prohibitive because of time constraints, but other methods of imaging lipid of water distributions (i.e., selective excitation, selective saturation, or variations in conventional magnetic resonance imaging pulse sequences) can provide chemical shift information. These techniques require less time, but they lack spectral information. Since fat deposition seen by chemical shift imaging may not be demonstrated by conventional magnetic resonance imaging, certain applications of chemical shift imaging, such as in the determination of fatty liver disease, have greater diagnostic utility than conventional magnetic resonance imaging. Furthermore, edge artifacts caused by chemical shift effects can be eliminated by certain selective methods of data acquisition employed in chemical shift imaging.
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PMID:Chemical shift imaging: a review. 300 43

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

Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus.
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PMID:Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance. 1693 11

Mitochondria are the major source of superoxide (O(2)(-)) in the aerobic organisms. O(2)(-) produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2(-/-)) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2(+/-)) show evidence of O(2)(-)-induced mitochondrial damage resembling cell senescence. Since earlier studies have provided compelling evidence for the role of oxidative stress and tubulointerstitial inflammation in the pathogenesis of hypertension, we tested the hypothesis that partial SOD2 deficiency may result in hypertension. Wild-type (SOD2(+/+)) and partial SOD2-deficient (SOD2(+/-)) mice had similar blood pressures at 6-7 mo of age, but at 2 yr SOD2(+/-) mice had higher blood pressure. Oxidative stress, renal interstitial T-cell and macrophage infiltration, tubular damage, and glomerular sclerosis were all significantly increased in 2-yr-old SOD2(+/-) mice. High-salt diet induced hypertension in 6-mo-old SOD2-deficient mice but not in wild-type mice. In conclusion, partial SOD2 deficiency results in oxidative stress and renal interstitial inflammation, changes compatible with accelerated renal senescence and salt-sensitive hypertension. These findings are consistent with the pattern described in numerous other models of salt-sensitive hypertension and resemble that commonly seen in elderly humans.
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PMID:Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence. 1702 72

Both chronic venous insufficiency (CVI) and fatty liver may develop at the same time. Hesperidin and diosmin are used for the treatment CVI. There is no information, however, on the effect of these flavonoids in the redox state of fatty liver. In this study, male Wistar albino rats were fed a lipid-rich diet with or without 450 mg diosmin-50 mg hesperidin-containing drug (60 mg kg(-1) body weight/day, per os) for 9 days to determine the impact of treatment on antioxidant defence system of the fatty liver. We detected free SH-group concentration (SHC), hydrogen-donating ability (HDA), and natural scavenger capacity were decreased and hepatic malonaldehyde content and dien conjugate (DC) content in rats with fatty liver were increased compared to the control. After treatment in fatty liver, these parameters (except DC) significantly improved and approached the control value. Our results indicate that diosmin-hesperidin-containing drug may be a useful agent in improving the antioxidant defensive system in alimentary-induced fatty liver disease.
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PMID:The effect of citrus flavonoids on the redox state of alimentary-induced fatty liver in rats. 1736 19

Recent extensive studies have revealed that molecular hydrogen (H(2)) has great potential for improving oxidative stress-related diseases by inhaling H(2) gas, injecting saline with dissolved H(2), or drinking water with dissolved H(2) (H(2)-water); however, little is known about the dynamic movement of H(2) in a body. First, we show that hepatic glycogen accumulates H(2) after oral administration of H(2)-water, explaining why consumption of even a small amount of H(2) over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H(2). Next, we examined the benefit of ad libitum drinking H(2)-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H(2)-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H(2)-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H(2)-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H(2)-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H(2) stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H(2) in improving obesity, diabetes, and metabolic syndrome.
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PMID:Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. 2129 45

A fundamental observation in biology is that mitochondrial function, as measured by increased reactive oxygen species (ROS), changes significantly with age, suggesting a potential mechanistic link between the cellular processes governing longevity and mitochondrial metabolism homeostasis. In addition, it is well established that altered ROS levels are observed in multiple age-related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, and cardiac disease, to name just a few. Manganese superoxide dismutase (MnSOD) is the primary mitochondrial ROS scavenging enzyme that converts superoxide to hydrogen peroxide, which is subsequently converted to water by catalase and other peroxidases. It has recently been shown that MnSOD enzymatic activity is regulated by the reversible acetylation of specific, evolutionarily conserved lysine(s) in the protein. These results, suggest for the first time, that the mitochondria contain bidirectional post-translational signaling networks, similar to that observed in the cytoplasm and nucleus, and that changes in lysine acetylation alter MnSOD enzymatic activity. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity / sensing protein, SIRT3, responds to changes in mitochondrial nutrient and/or redox status to alter the enzymatic activity of specific downstream targets, including MnSOD that adjusts and/or maintains ROS levels as well as metabolic homeostatic poise.
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PMID:Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. 2138 37


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