Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. In contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNFalpha protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis.
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PMID:The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury. 1803 73

Oxidative stress is suggested to play a key role in the development of alcoholic liver injury. We investigated the induction of oxidative damage in association with changes in hepatic concentrations of sulfur-containing substances in mice challenged with binge-like ethanol administration. Also the protective effect of dietary betaine against ethanol-induced liver injury was determined. Serum alanine aminotransferase activity, TNFalpha level, and hepatic malondialdehyde level were increased significantly by ethanol administration. Hepatic Cyp2e1 was induced to 250% of control. Ethanol administration decreased hepatic S-adenosylmethionine, cysteine, and glutathione, but elevated hypotaurine and taurine levels. Betaine supplied in drinking water for 2 weeks attenuated the induction of alcoholic liver injury and Cyp2e1 significantly. Reduction of hepatic S-adenosylmethionine and glutathione was alleviated, and elevation of hypotaurine and taurine was depressed. The results suggest that betaine may protect the liver against ethanol-induced oxidative injury most probably via its effects on the sulfur-amino acid metabolism.
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PMID:Alleviation of acute ethanol-induced liver injury and impaired metabolomics of S-containing substances by betaine supplementation. 1826 8

Acetaminophen (APAP) elicits hepatotoxicity via multifactorial pathways, including increased apoptosis, cyclooxygenase (Cox-2) generation, reactive metabolite release, and glutathione (GSH) depletion. We previously showed that mice that consumed different antioxidants in their diets were protected against APAP-induced hepatotoxicity. We therefore further investigated the mechanisms by which green-tea polyphenols (GrTP) protect against APAP-induced hepatic damage. Mice were administered a diet supplemented with GrTP or vehicle for 5 consecutive days followed by intraperitoneal (IP) injection of a toxic dose of APAP or sham. APAP administration upregulated Cox-2 and B-cell lymphoma-2 (Bcl-2) production and had an effect, albeit minor, on Cox-1 and Fas expression in hepatic tissue. GrTP supplementation normalized APAP induced Cox-2 expression and Bcl-2 activation (P < 0.01), as evidenced by immunohistochemistry and Western blot analyses. Similarly, APAP administration elicited marked depletion (99%) in hepatic reduced GSH (rGSH) and endogenous S-adenosylmethionine (SAMe) concentrations (twofold) when compared with sham. APAP also caused severe centrilobular apoptosis and necrosis accompanied by leukocyte infiltration and marked elevations in the hepatic enzyme, alanine aminotransferase (ALT) released from damaged hepatocytes, and cytokine tumor necrosis factor alpha (TNF-alpha). GrTP improved hepatic histopathology (P < 0.01) and attenuated ALT activity (P < 0.05) and the depletion of rGSH (P < 0.05). In conclusion, GrTP supplementation attenuated hepatotoxicity by normalizing Cox-2 and Bcl-2 activation, suggesting a potential use for GrTP in treatng APAP toxicity.
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PMID:Green-tea polyphenols downregulate cyclooxygenase and Bcl-2 activity in acetaminophen-induced hepatotoxicity. 1837 99

We examined the effect of taurine depletion on hepatic sulfur-containing amino acid metabolism and carbon tetrachloride-induced acute liver injury. Mice were supplemented with beta-alanine (3%) in drinking water for one week. beta-Alanine intake significantly reduced hepatic taurine levels, but did not influence S-adenosylmethionine, S-adenosylhomocysteine, glutathione levels or methionine adenosyltransferase activity in liver. However, hepatic cysteine levels were significantly elevated by beta-alanine administration. Hepatotoxicity caused by carbon tetrachloride (50 microl/kg, ip) in mice fed beta-alanine was decreased, as determined by changes in serum aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase activities. Hepatic glutathione and taurine levels after a carbon tetrachloride challenge were markedly increased by beta-alanine exposure. The results suggest that enhanced availability of cysteine for synthesis of glutathione and/or taurine may account for the hepatoprotective effects of beta-alanine against carbon tetrachloride-induced acute liver injury.
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PMID:Taurine depletion by beta-alanine inhibits induction of hepatotoxicity in mice treated acutely with carbon tetrachloride. 1923 61

Hyperhomocysteinemia has been correlated with hepatic steatosis and activation of the unfolded protein response (UPR), yet a causal relationship has not been established. Although methionine and choline are essential components of homocysteine metabolism, the role of homocysteine in the pathogenesis of a methionine- and choline-deficient (MCD) diet remains unknown. We explored the effects of homocysteine supplementation on hepatic steatosis and the UPR in mice fed a control or MCD diet. Mice fed the MCD diet developed severe hyperhomocysteinemia and activation of the hepatic UPR. Supplementing the MCD diet with homocysteine attenuated the MCD diet-induced hepatic UPR activation and other injurious effects of the MCD diet including hepatic cholesterol accumulation, weight loss, and plasma ALT elevation. Homocysteine supplementation replenished the MCD diet-induced depletion of hepatic S-adenosylmethionine (SAM). Depleting SAM in HepG2 cells using MAT1alpha siRNA or cycloleucine resulted in enhanced activation of the UPR upon exposure to thapsigargin. Mice fed a control diet supplemented with homocysteine had a 3-fold elevation in plasma homocysteine level by 2 weeks and 6-fold elevation by 6 weeks but demonstrated no other pathophysiologic change. In summary, we found that homocysteine attenuates MCD diet-induced hepatic UPR activation, likely via repletion of hepatic SAM. Furthermore, homocysteine supplementation alone does not cause hepatic steatosis or UPR activation despite inducing hyperhomocysteinemia. These studies indicate that although hyperhomocysteinemia is often associated with hepatic steatosis and UPR activation, these effects may be a secondary response rather than a direct effect of homocysteine.
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PMID:Homocysteine supplementation attenuates the unfolded protein response in a murine nutritional model of steatohepatitis. 1976 18

We have used a murine model of Acetaminophen induced hepatoxicity to determine if S-adenosyl methionine 1,4 butanedisulfonate (SD4) in liposomes can prevent liver injury when administered immediately prior to acetaminophen, as judged by serum aspartate aminotransferase and alanine aminotransferase levels, and histological evidence of liver necrosis. No protection was observed when mice received 1 g/kg unencapsulated SD4. Partial protection was observed with 5 or 0.5 mg/kg SD4 in unextruded distearoylphosphatidylglycerol (DSPG) liposomes. Protection comparable to that seen in mice receiving encapsulated SD4 is achieved when mice received lipid alone in equivalent amounts, suggesting that the contribution of encapsulated SD4 to the efficacy of the liposomes may be minimal. Unextruded distearoylphosphatidylcholine (DSPC) liposomes show only slight effects even at 50 mg/kg SD4. This is likely caused by the size of unextruded DSPC lipsomes, because extruded DSPC liposomes, whose size is smaller, are of comparable efficacy to unextruded DSPG liposomes.
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PMID:Evaluation of phospholipid and liposomal S-adenosyl methionine for the treatment of liver injury in a murine model. 1978 Jan 35

Cholestatic liver injury following extra- or intrahepatic bile duct obstruction causes nonparenchymal cell proliferation and matrix deposition leading to end-stage liver disease and cirrhosis. In cholestatic conditions, nitric oxide (NO) is mainly produced by a hepatocyte-inducible NO synthase (iNOS) as a result of enhanced inflow of endotoxins to the liver and also by accumulation of bile salts in hepatocytes and subsequent hepatocellular injury. This study was aimed to investigate the role of NO and S-nitrosothiol (SNO) homeostasis in the development of hepatocellular injury during cholestasis induced by bile duct ligation (BDL) in rats. Male Wistar rats (200-250 g) were divided into four groups (n=10 each), including sham-operated (SO), bile duct-ligated (BDL), tauroursodeoxycholic acid (TUDCA, 50 mg/kg) and S-methylisothiourea (SMT, 25 mg/kg) treated. After 7 days, BDL rats showed elevated serum levels of gamma-glutamiltranspeptidase, aspartate aminotransferase, alanine aminotransferase, LDH, and bilirubin, bile duct proliferation and fibrosis, compared with the SO group. TUDCA treatment did not significantly alter these parameters, but the iNOS inhibitor SMT ameliorated hepatocellular injury, as shown by lower levels of circulating hepatic enzymes and bilirubin, and a decreased grade of bile duct proliferation and fibrosis. Both TUDCA and SMT treatments reversed Mrp2 canalicular pump expression to control levels. However, only SMT treatment significantly lowered the increased levels of plasma NO and S-nitrosation (S-nitrosylation) of liver proteins in BDL rats. Moreover, BDL resulted in a reduction of the S-nitrosoglutathione reductase (GSNOR/Adh5) enzymatic activity and a downregulation of the GSNOR/Adh5 mRNA expression that was reverted by SMT, but not TUDCA, treatment. A total of 25 liver proteins, including S-adenosyl methionine synthetase, betaine-homocysteine S-methyltransferase, Hsp90 and protein disulfide isomerase, were found to be S-nitrosated in BDL rats. In conclusion, the inhibition of NO production during induced cholestasis ameliorates hepatocellular injury. This effect is in part mediated by the improvement of cell proficiency in maintaining SNO homeostasis.
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PMID:Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis. 1980 79

Enhanced oxidative stress is associated with hepatic fibrosis. Salvianolic acids A (Sal A) and B (Sal B) have been reported to be strong polyphenolic antioxidants and free radical scavengers. The present study is to investigate if Sal A and B could attenuate oxidative stress and liver fibrosis in rats. A cell line of rat hepatic stellate cells (HSCs) was stimulated with platelet-derived growth factor (PDGF, 10 ng/ml). The inhibitory effects of Sal A and B on intracellular hydrogen peroxide levels were measured with dichlorofluorescein diacetate (DCF-DA) dye assay. alpha-Smooth muscle actin (alpha-SMA), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits were measured by Western blotting. Liver fibrosis was induced by intraperitoneal injections of thioacetamide (TAA, 200 mg/kg) twice per week for 6 weeks. Sal A (10 mg/kg), Sal B (50 mg/kg) or S-adenosylmethionine (SAMe, 10 mg/kg), was given by gavage twice per day consecutively for 4 weeks starting 2 weeks after TAA injection. In vitro, PDGF increased the accumulation of hydrogen peroxide in HSCs, which was attenuated by Sal A (10 muM) and Sal B (200 muM). Sal A and B attenuated the PDGF-stimulated expressions of alpha-SMA and NADPH oxidase subunits gp91(phox) and p47(phox) in membrane fractions. In vivo studies showed that the hepatic levels of collagen, malondialdehyde, TNF-alpha, IL-6, and IL-1beta, fibrosis scores and protein expressions of alpha-SMA, heme-oxygenase-1, iNOS, and gp91(phox), and serum levels of ALT, AST, IL-6, and IL-1beta were increased in TAA-intoxicated rats, all of which were attenuated by 4-week treatment of Sal A or Sal B. Our results showed that Sal A and B attenuated PDGF-induced ROS formation in HSCs, possibly through inhibition of NADPH oxidase. Sal A and B treatments were also effective against hepatic fibrosis in TAA-intoxicated rats.
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PMID:Effects of salvianolic acids on oxidative stress and hepatic fibrosis in rats. 1982 64

Chronic ethanol ingestion, achieved by feeding ethanol at a constant rate using intragastric tube feeding, alters the expression of genes in the liver. This is done by epigenetic mechanisms, which depend on the blood alcohol levels at the time of killing. However, acute bolus feeding of ethanol changes gene expression without lasting epigenetic changes. This occurs with histone 3 methylation and acetylation modifications. The gene expression response to an acute bolus of ethanol might be modified by feeding S-adenosylmethionine (SAMe), a methyl donor. In the present study, rats were given a bolus of ethanol (6 g/kg body weight (bw), SAMe (1 g/kg bw), ethanol + SAMe, or isocaloric glucose. The group of rats (n = 3) were killed at 3 and 12 h post bolus, and gene microarray analysis was performed on their liver cells. SAMe reduced the 3 h blood ethanol levels and increased the ALT levels at 3 h. Venn diagrams showed that alcohol changed the expression of 646 genes at 3 h post bolus and 586 genes at 12 h. SAMe changed the expression of 1,012 genes when fed with ethanol 3 h post ethanol bolus and 554 genes at 12 h post ethanol bolus. SAMe alone changed the expression of 1,751 genes at 3 h and 1,398 at 12 h. There were more changes in gene expression at 3 h than at 12 h post ethanol when ethanol alone was compared to the dextrose control. The same was true when SAMe was compared to SAMe + ethanol. Ethanol up regulated gene expression in most functional pathways at 3 h. However, when SAMe was fed with ethanol at 3 h, most pathways were down regulated. At 12 h, however, when ethanol was fed, the pathways were half up regulated and half down regulated. The same was true when SAMe + ethanol was fed. The expression of epigenetically important genes, such as BHMT and Foxn3, was up regulated 3 h post alcohol bolus. At 3 h, SAMe down regulated the expression of genes, such as BHMT, Mat2a, Jun, Tnfrs9, Ahcy 1, Tgfbr1 and 2, and Pcaf. At 12 h, the insulin signaling pathways were half down regulated by ethanol, which was partly prevented by SAMe. The MAPK pathway was up regulated by ethanol, but SAMe did not prevent this. In conclusion, profound changes in gene expression evolved between 3 h and 12 post ethanol bolus. SAMe down regulated these changes in gene expression at 3 h, and less so at 12 h.
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PMID:Gene expression modifications in the liver caused by binge drinking and S-adenosylmethionine feeding. The role of epigenetic changes. 1996 Feb 81

S-adenosylmethionine (SAMe), the major methyl donor for DNA and histone methylation was fed with ethanol for 1month in order to modify the effects of ethanol on rat liver. The following parameters were studied to determine the effects of SAMe; liver histology, the blood alcohol cycle (BAL), changes in gene expression mined from microarray analysis, changes in histone methylation, changes in liver SAMe levels and its metabolites and ADH. SAMe changed the type of fatty liver, reduced liver ALT levels and prevented the BAL cycle caused by intragastric ethanol feeding. Microarray analysis showed that SAMe feeding prevented most of the changes in gene expression induced by ethanol feeding, presumably by inducing H3K27me3 and gene silencing. H3K27me3 was significantly increased by SAMe with or without ethanol feeding. It is concluded that SAMe feeding stabilized global gene expression so that the changes in gene expression involved in the blood alcohol cycle were prevented.
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PMID:The cyclic pattern of blood alcohol levels during continuous ethanol feeding in rats: the effect of feeding S-adenosylmethionine. 2030 46


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