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)

The relationship between hepatic glycerolipids and microsomal drug-metabolizing enzymes was studied in liver biopsies from 41 subjects. The series included obese, diabetic, epileptic and chronic alcoholic patients, all of whom were hospitalized for suspected hepatic ailments (fatty liver, hepatitis or cirrhosis). Therapy with enzyme-inducing anticonvulsants was associated with high phospholipid and cytochrome P-450 and low triacylglycerol concentration in the liver. In patients with fatty liver or cirrhosis low phospholipid and cytochrome P-450 and high triacylglycerol concentrations were observed. There was a significant correlation (r (Pearson's product moment correlation coefficient) = 0.91) between the hepatic phospholipid and cytochrome P-450 concentration. The cytochrome P-450 concentration was inversely related (r = -0.74) to the triacylglycerol concentration. The positive correlation between hepatic phospholipids and drug-metabolizing enzymes could be interpreted as indicating that in human liver phospholipid and cytochrome P-450 synthesis share common regulators, or that phospholipids are necessary for the maximum rate of cytochrome P-450 synthesis.
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PMID:Relationship between lipid composition and drug metabolizing capacity of human liver. 398 78

Three experiments were conducted to investigate the effect of diet and estradiol (E2) administration on hepatic microsomal mixed function oxidase (MFO) activity, E2 metabolism, and liver lipid content in male broiler chicks. Broiler chicks (3 weeks of age) were fed either a corn-soybean (CS) diet or a diet containing fish meal, alfalfa meal, and torula yeast (FAY) for 19 days in Experiments 1 and 3 and for 14 days in Experiment 2, respectively. Half of the chicks were implanted with tubes containing E2. In all experiments when the chicks were estrogenized, feeding FAY significantly lowered liver lipid content and plasma E2 concentration. Activity of hepatic microsomal aniline hydroxylase and content of cytochrome P-450 were significantly increased by feeding FAY with or without E2 administration. The chicks fed the CS diet had a significantly lower content of cytochrome P-450 when E2 was administered. Activities of aminopyrine demethylase and nicotinamide adenine dinucleotide phosphate, reduced (NADPH)-cytochrome C reductase did not differ significantly between the diets. In in vitro studies, conversion of 14C-E2 into the water soluble fraction was significantly increased in microsomes from chicks fed the FAY diet as compared to ones from chicks fed the CS diet. The results suggest that some of the hepatic microsomal functions on the CS diet are modified by the change in diet composition and that these modifications are probably associated with E2 metabolism and occurrence of fatty liver.
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PMID:Effect of dietary composition and estradiol implants on hepatic microsomal mixed function oxidase and lipid deposition in growing chicks. 651 66

The relationship between blood lactate levels, liver histology and microsomal enzyme activity (cytochrome P-450 content) was assessed in 32 non-insulin-dependent diabetics (NIDD) undergoing diagnostic liver biopsy. Fasting blood lactate was related to liver histology and the mean was in the low normal range in the diabetics with an intact liver, whereas higher values were noted in the diabetics with a fatty liver, inflammatory changes and an increase in fibrous trabeculae. Similarly, in the diabetics with an abnormal liver, there was a tendency for pyruvate to be elevated, and body weights and serum insulin concentrations were higher than in the NIDD with an intact liver. P-450 was inversely related to liver histology and its content was reduced in association with increases in fat and fibrous tissues. P-450 was significantly correlated with lactate (rs -0.79), pyruvate (rs -0.65) and serum insulin (rs -0.53). The results revealed close associations between blood lactate, hepatic structure and microsomal enzyme activity, and emphasize that liver function is an important consideration when lactate metabolism is evaluated in NIDD.
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PMID:Blood lactate, hepatic histology and microsomal enzyme activity in non-insulin-dependent diabetics. 661 29

The first step in ethanol metabolism is carried out by two enzyme systems: Alcohol dehydrogenase and cytochrome P-450. The cytochrome P-450 system also detoxifies a wide variety of foreign compounds. On the basis of recent evidence, metabolic reasons are suggested for four well-known consequences of alcoholism: (a) The development of fatty liver; (b) the development of metabolic tolerance; (c) the occurrence of interactions between drugs and alcohol; and (d) the fact that many of the kilocalories attributable to ethanol do not seem to "count "count "count" when ethanol forms a major part of the diet.
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PMID:Metabolism of ethanol. 677 4

Hepatic drug-metabolizing capacity was investigated in 56 diabetics. The antipyrine test was selected as an in vivo index, since its kinetics indirectly reflect the metabolically active liver mass. Hepatic cytochrome P-450 (P-450), determined from the biopsy samples, was used as an in vitro parameter, since it is a direct measure of microsomal drug-metabolizing enzyme activity. There was a wide interindividual variation in the indexes of drug metabolism in the diabetics: 40 fold in P-450 content and eightfold in antipyrine metabolism. P-450 levels were higher and antipyrine metabolism faster in the subjects with normal liver than in those with fatty liver, parenchymal inflammatory changes, or cirrhosis. Thus the in vivo and in vitro parameters of drug metabolism were related to the alterations in liver histology. On the other hand, the diabetes per se did not seem to alter the drug-metabolizing capacity of the liver. Also, drug metabolism in diabetics classified by treatment regimen did not differ significantly.
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PMID:The evaluation of the drug-metabolizing capacity in patients with diabetes mellitus. 743 38

Liver fatty acid-binding protein (L-FABP) expression is modulated by developmental, hormonal, dietary, and pharmacological factors. The most pronounced induction is seen after treatment with peroxisome proliferators, which induce L-FABP coordinately with microsomal cytochrome P-450 4A1 and the enzymes of peroxisomal fatty acid beta-oxidation. These effects of peroxisome proliferators may be mediated by a receptor which has been shown to be activated by peroxisome proliferators in mammalian cell transfection studies. However, the peroxisome proliferators tested thus far do not bind to this receptor, known as the peroxisome proliferator-activated receptor (PPAR), and its endogenous ligand(s) also remain unknown. Peroxisome proliferators inhibit mitochondrial beta-oxidation, and one hypothesis is that the dicarboxylic fatty acid metabolites of accumulated LCFA, formed via the P-450 4A1 omega-oxidation pathway, serve as primary inducers of L-FABP and peroxisomal beta-oxidation. We have tested this hypothesis in primary hepatocyte cultures exposed to clofibrate (CF). Inhibition of P-450 4A1 markedly diminished, via a pre-translational mechanism, the CF induction of L-FABP and peroxisomal beta-oxidation. In further experiments, long-chain dicarboxylic acids, the final products of the P-450 4A1 omega-oxidation pathway, but not LCFA, induced L-FABP and peroxisomal beta-oxidation pre-translationally. These results suggest a role, in part, for long-chain dicarboxylic acids in mediating the peroxisome proliferator induction of L-FABP and peroxisomal beta-oxidation. We also found that LCFA, which undergo rapid hepatocellular metabolism, could become inducers of L-FABP and peroxisomal beta-oxidation under conditions where their metabolism was inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of regulation of liver fatty acid-binding protein. 823 72

Alcohol was administered chronically to female Sprague Dawley rats in a nutritionally adequate totally liquid diet for 28 days. This resulted in hepatic steatosis and lipid peroxidation. Taurine, when co-administered with alcohol, reduced the hepatic steatosis and completely prevented lipid peroxidation. The protective properties of taurine in preventing fatty liver were also demonstrated histologically. Although alcohol was found not to affect the urinary excretion of taurine (a non-invasive marker of liver damage), levels of serum and liver taurine were markedly raised in animals receiving alcohol + taurine compared to animals given taurine alone. The ethanol-inducible form of cytochrome P-450 (CYP2E1) was significantly induced by alcohol; the activity was significantly lower than controls and barely detectable in animals fed the liquid alcohol diet containing taurine. In addition, alcohol significantly increased homocysteine excretion into urine throughout the 28 day period of ethanol administration; however, taurine did not prevent this increase. There was evidence of slight cholestasis in animals treated with alcohol and alcohol + taurine, as indicated by raised serum bile acids and alkaline phosphatase (ALP). The protective effects of taurine were attributed to the potential of bile acids, especially taurine conjugated bile acids (taurocholic acid) to inhibit the activity of some microsomal enzymes (CYP2E1). These in vivo findings demonstrate for the first time that hepatic steatosis and lipid peroxidation, occurring as a result of chronic alcohol consumption, can be ameliorated by administration of taurine to rats.
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PMID:Taurine: protective properties against ethanol-induced hepatic steatosis and lipid peroxidation during chronic ethanol consumption in rats. 987 87

Cytotoxicity and apoptosis are common problems in the isolation and storage of human hepatocytes. In vitro environments of hepatocytes during cell infusion may be critical to reducing cellular damage and enhancing cell viability. We examined the effects of donor liver histology (40-50% steatosis vs. normal), incubation time, temperature, and three solutions for infusion on banked primary human hepatocytes, by studying: trypan blue exclusion, AST release, LDH release, MTT assay, detection of DNA ladder, and a hepatocyte proliferation assay. In addition, the microstructure functions of the endoplasmic reticulum and mitochondria of the intact hepatocytes were determined by measuring correlates of UGT 1A1 and cytochrome P-450 3A (CYP3A4) activity. In general, hepatocyte viability decreased significantly within 60 min after thawing. Cells suspended in 5% dextrose lactated Ringers solution (D5LR) maintained greater cell viability. Hepatocytes from normal liver donors showed less AST and LDH enzyme leak in comparison with cells from fatty liver donors. Mild hypothermic temperature (32 degrees C) inhibited cellular damage that otherwise significantly increased at 60 min. Hepatocytes did not proliferate until 12 h from thaw, regardless of supernatant or conditions of suspension. CYP3A4 activity and a marker for UGT 1A1 activity in hepatocytes from normal donor livers were higher than those from steatotic donor livers. These findings suggest that hepatocytes suspended for infusion after isolation from normal liver donors have normal biological functions and less cellular damage/necrosis in contrast with those isolated from fatty liver donors. These damages are inhibited significantly by maintaining hepatocytes at a mild hypothermic temperature (32 degrees C). D5LR alone maintained the best cell viability for up to 60 min. Media of D5LR + adenosine and HMM were able to partially inhibit hepatocyte apoptosis in hepatocytes from steatotic livers.
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PMID:Optimization of conditions for clinical human hepatocyte infusion. 1564 38

Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome. The metabolic syndrome is characterized by insulin resistance, which is produced by a complex interaction between genetic factors, macronutrient intake and lifestyle that alters the cytokine profile, cell biology and biochemical milieu of the liver, adipose tissue and striated muscle. The resultant disequilibrium in lipid homeostasis causes triglycerides to accumulate in the liver. An increase in oxidative stress, due to the generation of reactive oxygen species as a result of mitochondrial abnormalities and induction of the cytochrome P-450 system could be one mechanism by which the nonalcoholic fatty liver develops into nonalcoholic steatohepatitis. The pathogenesis of cytologic ballooning and Mallory body formation and their role in NAFLD remain to be defined. In addition, inflammation and fibrosis are likely to be secondary to hepatocyte injury and death.
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PMID:Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease. 1626

Non-alcoholic fatty liver disease (NAFLD) is emerging as a common medical problem. Nonalcoholic steatohepatitis (NASH) is the critical turning point at which NAFLD progresses to more advanced stages such as hepatic fibrosis, cirrhosis and even hepatocellular carcinoma. However, the study of the pathogenic or therapeutic factors involved in NASH has been hampered by the absence of a suitable experimental model. The aim of the present work was to establish a high-fat emulsion-induced rat model of NASH. Male Sprague-Dawley rats were fed a high-fat emulsion via gavage for 6 weeks. Animals were examined for weight gain, serum and hepatic biochemistry, insulin sensitivity, hepatic malondialdehyde (MDA), superoxide dismutase (SOD) and tissue morphology, as well as cytochrome P-450 2E1 (CYP2E1) and peroxisome proliferator-activated receptor alpha (PPARalpha) expression in the liver. The results showed that rats treated with high-fat emulsion became obese, demonstrated abnormal aminotransferase activity, hyperlipoidemia, hyperinsulinemia, hyperglycemia and insulin resistance. The model rats exhibited an increased concentration of serum TNF-alpha, total cholesterol (TC), triglyceride (TG), MDA and reduced SOD levels in the liver. Immunoblot analysis showed that the expression of CYP2E1 was increased, whereas PPARalpha was reduced in the NASH model rat liver. Moreover, morphological evaluation revealed that hepatic steatosis, inflammation and mitochondrial lesions were also reproduced in this model. In conclusion, a practical and repeatable new rat model of steatohepatitis was established by feeding with high-fat emulsion via gavage. This model provides a valuable research tool and reproduces many of the clinical indices of human NASH.
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PMID:High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. 1662 32


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