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 enzyme systems aldehyde dehydrogenase (ALDH), formaldehyde dehydrogenase (FDH) and S-formylglutation dehydrogenase (FGH/ESD) were investigated in specimen of cadaveric liver and brain by semiquantitative adjusted starch gel electrophoresis. Two groups of autopsy cases were compaired 1. alcoholics with fatty liver and 2. nonalcoholics. In ALDH and FDH there were no differences between the examined groups. In about 48% of specimens of alcoholics were in a more or less degree alterations in phenotypes of ESD detectable in vitro experiments showed that ESD spots were modified and became less intensive in the presence of formaldehyde (0.5-2.5 mg/g). These alterations were more intensiv in the phenotyp ESD 1 then in the phenotyp ESD 2-1.
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PMID:[Aldehyde metabolizing enzymes in the central nervous system and liver--electrophoresis studies of alcoholism]. 181 91

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

Alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and P450IIE1 are the primary enzymes that catalyze the conversion of ethanol to acetaldehyde and then to acetate. Genetic polymorphisms have been reported in ADH2, ADH3, ALDH2, and the 5'-flanking region of P450IIEI. In this study, we used multivariate analysis to determine which genetic polymorphisms in alcohol metabolizing enzymes were independently associated with the development of alcoholic cirrhosis. Thirty-four noncirrhotic alcoholic patients, including 27 with fatty liver and 7 with nonspecific changes, and 46 patients with alcoholic liver cirrhosis were studied. Restriction fragment length polymorphisms (RFLPs) in the ADH2 and P450IIE1 genes were detected by digestion of polymerase chain reaction (PCR)-amplified DNA with MaeIII and RsaI, respectively. In the ALDH2 gene, RFLPs were detected by differences in the MboII site after PCR amplification. By multivariate analysis of four significant factors including total alcohol intake, ADH, ALDH, and P450IIE1 using the multiple logistic regression model, genotype ADH2(2)/ADH2(2) (P = .029) and genotype c1/c1 of P450IIE1 (P = .013) were found to be independently associated with alcoholic cirrhosis. The odds ratios for ADH2(2)/ADH2(2) genotype and the type A genotype of P450IIE1 (c1/c1) were 4.600 and 4.006, respectively. These results suggest that ADH2 and P450IIE1 gene polymorphisms may be independently associated with the development of alcoholic liver cirrhosis in Japan.
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PMID:Polymorphisms in alcohol metabolizing enzyme genes and alcoholic cirrhosis in Japanese patients: a multivariate analysis. 870 76

We prepared low-density lipoprotein (LDL)-acetaldehyde-adduct (hereafter abbreviated as LDL-adduct) and anti-LDL-adduct antibody by using Watanabe hyperlipidemic rabbits, and determined values of serum anti-LDL-adduct antibody levels by the ELISA method in healthy adults and patients with alcoholic liver injury. In the nondrinking group in healthy adults, values of anti-LDL-adduct antibody levels were 25 +/- 13 microg/ml, and there was no significant difference between moderate drinkers without diseases and the nondrinking group in healthy adults. Values of anti-LDL-adduct antibody in alcoholic disease groups, 17 +/- 9 microg/ml for the patients with the fatty liver group, 21 +/- 14 microg/ml for the hepatic fibrosis group, 70 +/- 21 microg/ml for the alcoholic hepatitis group, 41 +/- 50 microg/ml for the alcoholic cirrhosis group, and 19 +/- 18 microg/ml for the alcoholic pancreatitis group. Examinations of aldehyde dehydrogenase 2 (ALDH2) genetic variations by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method in the healthy group and the liver injury group revealed a tendency for patients with ALDH2(1)/2(2) in the liver injury group to have relatively mild liver lesions. When comparing anti-LDL-adduct antibody levels between ALDH2 genetic variations, those for the patients with ALDH2(1)/2(2) (36 +/- 40 microg/ml) were significantly higher than those for patients with ALDH2(1)/2(2) (11 +/- 5 microg/ml). Results of the present study suggest that genetic variation may influence the progression of liver injury.
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PMID:Relationship between serum levels of anti-low-density lipoprotein-acetaldehyde-adduct antibody and aldehyde dehydrogenase 2 heterozygotes in patients with alcoholic liver injury. 1023 74

Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA-RH7777 hepatoma cell lines, ethanol induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter via increased levels of mature SREBP-1 protein. This effect of ethanol was blocked by addition of sterols. This effect is likely mediated by acetaldehyde, because the effect was only seen in cell lines expressing alcohol dehydrogenase, and inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect in the hepatoma cells. Furthermore, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells. Consistent with these in vitro findings, feeding mice a low fat diet with ethanol for 4 weeks resulted in a significant increase in steady-state levels of the mature (active) form of SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of hepatic lipogenic genes as well as the accumulation of triglyceride in the livers. These finding suggest that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver.
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PMID:Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP). 1203 55

Recent studies indicate that some patients with nonalcoholic fatty liver have ongoing liver injury that may progress from steatosis to steatohepatitis or fibrosis. The present study was designed to clarify the clinical features of liver dysfunction observed in the course of workplace physical check-ups in relation to multiple risk factor syndrome including obesity, hyperlipidemia, hypertension, and impaired glucose tolerance, and to clarify the involvement of aldehyde dehydrogenase 2 (ALDH2) and beta(3)-adrenergic receptor (beta3-AR) gene polymorphisms in elevation of liver enzymes. One hundred forty-eight male workers 35 years of age were enrolled. They were requested to answer questionnaires about drinking and smoking habits, and underwent urinalysis, physical and peripheral blood examinations, blood chemistry, electrocardiogram and chest x-rays. The genotypes of ALDH2 and beta3-AR were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The subjects were divided into active ALDH2 or inactive ALDH2 groups. They were also divided into 2 groups according to the beta3-AR genotype. The relationships between ALDH2 and beta3-AR gene polymorphism and the results of the physical examination including liver function tests were analyzed. The subjects were also divided according to the number of components of metabolic syndrome. The prevalence of elevated alanine aminotransferase (ALT) level increased with the accumulation of components of metabolic syndrome. Active ALDH2 was associated with elevated ALT level to a greater degree than beta3-AR polymorphism. Among those with normal body mass index (BMI), the genotypes of ALDH2 and beta3-AR were strongly associated with elevated ALT level. Logistic regression analysis revealed that BMI, triglyceride level, and ALDH2 genotype were associated with ALT elevation. In conclusion, evaluating the genotype of ALDH2 and beta3-AR may assist in predicting and preventing the development of fatty liver which may be related to multiple risk factor syndrome.
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PMID:Aldehyde dehydrogenase 2 and beta3-adrenergic receptor gene polymorphisms: their association with elevated liver enzymes and metabolic syndrome. 1450 13

Alcoholic steatosis (AS) is the initial pathology associated with early stage alcoholic liver disease (ALD) and is characterized by the accumulation of fat in the liver. AS is considered clinically benign because it is reversible, and the progression of AS to alcoholic steatohepatitis (ASH) is a key step in the development of ALD. A two-dimensional gel electrophoresis (2DE)-mass spectrometry (MS) proteomic approach was used to investigate the protein expression pattern underlying AS, as the first step toward determining liver tissue biomarkers for early stage ALD. Several proteins involved in fatty acid and amino acid metabolism were up-regulated in 3- and 6-week ethanol-fed rats relative to isocaloric controls, which suggest a higher energy demand upon chronic exposure to ethanol. In addition, the expression of two proteins associated with alcohol-induced oxidative stress, peroxiredoxin 6 (PRDX6) and aldehyde dehydrogenase 2 (ALDH2), was down-regulated in ethanol fed rats, and suggests an increase in reactive oxygen species and oxidative stress. To investigate if irreversible protein modification arising from oxidative stress during AS impacts protein levels, the extent of carbonylated proteins in the ethanol and isocaloric groups was identified using mass spectrometry. The detection of modified proteins involved in antioxidant functions further supports the notion that oxidative modification of these proteins leads to protein turnover during AS. In addition, the carbonylation of betaine-homocysteine S-methyltransferase, a protein implicated in fatty liver development, in 3-week and 6-week ethanol exposed samples suggests that this protein could be a marker for early stage AS.
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PMID:Liver proteome analysis in a rodent model of alcoholic steatosis. 1971 8

From the biomedical point of view alcohol is a Janus-faced dietary component with a dose-dependent effect varying from cardiovascular protection to cytotoxicity. Alcohol is absorbed in the upper gastrointestinal tract by passive diffusion, is quickly distributed throughout body water and is mostly eliminated through oxidation. The enzymatically-catalyzed oxidative degradation to acetaldehyde and further to acetate is primarily localized in the liver. In case of a low blood alcohol concentration (<0.5 per thousand) alcohol is predominantely metabolized by the enzyme aldehyde dehydrogenase; higher blood concentrations (>0.5 per thousand) are increasingly oxidized by the microsomal ethanoloxidizing system (MEOS). Alcohol consumption induces several metabolic reactions as well as acute effects on the central nervous system. Chronic alcohol consumption to some extent irreparably damages nearly every organ with the liver being particularly concerned. There are three stages of alcohol-induced liver disease (fatty liver, alcohol hepatitis, liver cirrhosis) and the liver damages mainly result from reaction products of alcohol degradation (acetaldehyde, NADH and reactive oxygen species). An especially dreaded clinical complication of the alcohol-induced liver disease is the hepatic encephalopathy. Its pathogenesis is a multifactorial and self-perpetuating process with the swelling of astrocytes being a crucial point. Swollen astrocytes induce several reactions such as oxidative/nitrosative stress, impaired signal transduction, protein modifications and a modified gene expression profile. The swelling of astrocytes and the change in neuronal activity are attributed to several neurotoxins, especially ammonia and aromatic amino acids. In alcohol addicted subjects multiple micronutrient deficiencies are common. The status of folic acid, thiamine, pyridoxine and zinc is especially critical.
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PMID:[Alcohol intake--a two-edged sword. Part 1: metabolism and pathogenic effects of alcohol]. 2297 May 27

Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber-DeCarli diet daily for 1 and 3 months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3 months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved in alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3 months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (-1.6) at 1 month and up regulation of aldehyde dehydrogenase (2.1) at 3 months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1 month) while peroxiredoxin-1 was down regulated (-1.5) at late fatty liver stage (3 months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified d-dopachrome tautomerase (-1.7, at 3 months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum.
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PMID:Liver proteomics in progressive alcoholic steatosis. 2320 Jul 77

The present research draws a map of the characteristic carbonylation of proteins in rats fed high-caloric diets with the aim of providing a new insight of the pathogenesis of metabolic diseases derived from the high consumption of fat and refined carbohydrates. Protein carbonylation was analyzed in plasma, liver and skeletal muscle of Sprague-Dawley rats fed a high-fat, high-sucrose (HFHS) diet by a proteomics approach based on carbonyl-specific fluorescence-labeling, gel electrophoresis and mass spectrometry. Oxidized proteins along with specific sites of oxidative damage were identified and discussed to illustrate the consequences of protein oxidation. The results indicated that long-term HFHS consumption increased protein oxidation in plasma and liver; meanwhile, protein carbonyls from skeletal muscle did not change. The increment of carbonylation by HFHS diet was singularly selective on specific target proteins: albumin from plasma and liver, and hepatic proteins such as mitochondrial carbamoyl-phosphate synthase (ammonia), mitochondrial aldehyde dehydrogenase, argininosuccinate synthetase, regucalcin, mitochondrial adenosine triphosphate synthase subunit beta, actin cytoplasmic 1 and mitochondrial glutamate dehydrogenase 1. The possible consequences that these specific protein carbonylations have on the excessive weight gain, insulin resistance and nonalcoholic fatty liver disease resulting from HFHS diet consumption are discussed.
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PMID:Protein carbonylation associated to high-fat, high-sucrose diet and its metabolic effects. 2528 56


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