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)

We previously reported a link between ethanol-induced elevation of homocysteine, endoplasmic reticulum (ER) stress, and alcoholic liver injury in the murine model of intragastric ethanol feeding. We studied the role of TNFalpha in this setting by using TNFR1 knockout mice (C57 BL/6). There was a 7.4-fold increase of homocysteine in wild-type and a 6-fold increase in TNFR1 knockout mice with intragastric alcohol exposure for 4 weeks. Plasma TNFalpha increased in the wild-type (18.4 +/- 3.3 pg/mL vs. 8.4 +/- 1.3 pg/mL (control)) and in the knockouts (12.9 +/- 1.4 pg/mL vs. 7.2 +/- 1.6 pg/mL (control)). Similar extent of fatty liver was observed in both types. Increased ALT was observed in both groups. Necroinflammatory foci were increased significantly in ethanol-fed knockouts but not to the same extent as in the ethanol-fed wild type. Increase of hepatic apoptosis and reduction of S-adenosyl-L-methionine was detected in both types of animals fed ethanol. ER stress demonstrated by RT-PCR of mRNA of selective ER stress markers GRP78, CHOP, and SREBP1 was increased equivalently in both types of mice. Betaine administration decreased ER stress in conjunction with attenuation of the elevated plasma homocysteine in both types of animals. Betaine increased hepatic S-adenosyl-L-methionine by 28 fold in the knockouts and by 24-fold in wild type. In conclusion, TNFalpha makes a moderate contribution to the ALT elevation, necroinflammation, apoptosis, a small contribution to the fatty liver and no contribution to hyperhomocysteinemia and ER stress in intragastric alcohol fed mice.
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PMID:Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. 1536 49

Hyperhomocysteinemia, a condition of elevated blood homocysteine level, is an independent risk factor for cardiovascular diseases. Hyperhomocysteinemia is also found in patients with liver diseases. However, the direct effect of homocysteine on liver injury is not well known. Folic acid supplementation is a promising approach for improving endothelial function in patients with hyperhomocysteinemia. The aim of this study was to investigate the direct effect of hyperhomocysteinemia on liver injury and whether folic acid could offer any protective effect to the liver. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 4 weeks. There was a significant increase in the serum aspartate aminotransferase and alanine aminotransferase activities reflecting liver injury in hyperhomocysteinemic rats. Hepatic NAD(P)H oxidase was activated during hyperhomocysteinemia leading to increased superoxide anion production and peroxynitrite formation in the liver. As a consequence, the level of lipid peroxides was significantly elevated in livers of hyperhomocysteinemic rats. Folic acid supplementation effectively inhibited NAD(P)H oxidase-mediated superoxide anion production leading to reduced lipid peroxidation in the liver. Folic acid supplementation also alleviated hyperhomocysteinemia-induced liver injury. These results suggest that hyperhomocysteinemia can cause liver injury and supplementation of folic acid offers a hepatoprotective effect.
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PMID:Hyperhomocysteinemia induces liver injury in rat: Protective effect of folic acid supplementation. 1683 72

It is documented that hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis, but whether elevated plasma homocysteine contributes to the progression of atherosclerosis in aged animals with hypercholesterolemia is still unknown. HHcy was induced in apolipoprotein E (ApoE) knockout mice (male, 32 weeks old) by feeding 2% methionine/low folate (1 mg/kg) diet for 20 weeks. HHcy induced by methionine feeding significantly increased oxidative stress, as measured by thiobarbituric-reactive substances in livers (P < .05) and genetic expression of Cu,Zn-superoxide dismutase, in methionine-fed animals compared with controls (P < .05). Furthermore, lipoprotein profiles were changed, in that low-density lipoprotein-cholesterol was shifted to very low-density lipoprotein in the methionine-supplemented group. However, nuclear factor kappaB activity, atherosclerotic lesions, hepatic glutathione level, lipid profiles, and activities of aspartate aminotransferase and alanine aminotransferase were not significantly different. These findings suggest that HHcy induced by methionine may promote disturbances in lipid peroxidation and modify lipoprotein metabolism but not contribute to the progression of atherosclerotic lesion in aged ApoE knockout mice.
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PMID:Methionine-induced hyperhomocysteinemia modulates lipoprotein profile and oxidative stress but not progression of atherosclerosis in aged apolipoprotein E knockout mice. 1929 7

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

Our previous study found that Chinese yellow wine could inhibit the production of homocysteine (HCY) induced extracellular matrix metalloproteinase-2 (MMP-2) in the cultured rat vascular smooth muscle cells. Little is known about the relationship between Chinese yellow wine and atherosclerosis or MMP-2 in vivo. Thirty-two LDL Receptor knockout mice on a high-fat and L-methionine diet developed plasma hyperhomocysteinemia and atherosclerosis. They were randomly divided into yellow wine group (n = 8), red wine group (n = 8), ethanol group (n = 8), and control group (n = 8), they were sacrificed after 14 weeks. There were no significant differences with plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in the four groups. Plasma HCY was significantly decreased in the yellow wine group compared to the other three groups (P < 0.01). Yellow wine and red wine groups significantly reduced the atherosclerosis lesion area compared to ethanol and control groups (P < 0.001). However, there was no significant discrepancy between the yellow wine group and red wine group. Compared to the control group and ethanol group, the production of MMP-2 reduced 26.8% and 23.6% in the aortic sinus and the activation of MMP-2 reduced 32.6% and 27.3% in the aortic arch in the yellow wine group; the production of MMP-2 reduced 25.7% and 22.4% in the aortic sinus and the activation of MMP-2 reduced 30.2% and 26.6% in the aortic arch in the red wine group. These results suggest that Chinese yellow wine and red wine can inhibit MMP-2 and improve atherosclerosis, and maybe both Chinese yellow wine and red wine have beneficial effects on cardiovascular disease by inhibiting MMP-2.
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PMID:Chinese yellow wine and red wine inhibit matrix metalloproteinase-2 and improve atherosclerotic plaque in LDL receptor knockout mice. 2037 Jul 96

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612(**)), AST (r = 0.652(*)), CD (r = 0.495(*)), and TRAP (r = -0.486(*)). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress.
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PMID:Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol. 2225 76

Oxidative stress in utero-placental tissues plays an important role in the development of placental-related diseases. Maternal hiperhomocysteinemia is associated with placental mediated diseases, such as preeclampsia, spontaneous abortion and placental abruption. The aim of our study is to appreciate the clinical usefulness of the dosage serum homocysteine and malondialdehyde, as an oxidative stress marker, in the pregnancies complicated with risk of abortion or preterm birth. The study was performed at the Obstetric Gynecology Clinical Hospital Oradea from December 2009 until April 2010. It included 18 patients with risk of abortion (group 1), 22 with preterm birth (group 2). The results were compared with a control group composed by 14 healthy pregnant women. Serum homocysteine level was measured by an enzymatic method, on the instrument Hitachi 912, Roche, reagent: Axis-Shield Enzymatic. For proving the oxidative stress we established the level of malondialdehyde using a method with thiobarbituric acid TBA (Kei Satoh 1978) and the level of ceruloplasmin with the Ravin method .Also AST, ALT,CRP, iron, uric acid, urea were assessed.High level of homocysteine in both groups of study in comparison with the control group was found. The concentration of MDA was significantly higher in pregnancies complicated with risk of abortion and preterm birth compared to the control group (p=0.040, p=0.031). Considerable differences of ceruloplasmin concentration between group 1 and group 2 (p=0.045), and between group 2 and control group (p=0.034), was noticed but not any important differences between group 1 and control group (p=0.683). In women with risk of abortion or with preterm birth an oxidative stress and a hyperhomocysteinemia are present.
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PMID:The influence of homocysteine and oxidative stress on pregnancy outcome. 2257 89

This study is conducted in chronic alcoholics to assess the association of an Individual's level of serum homocysteine with the success of achieving alcohol deaddiction in the patient. The patients' nutrition status is also assessed. 50 chronic alcoholics admitted to a deaddiction center were inducted into the study. Patients underwent an 8 weeks holistic program to promote rehabilitation from alcoholism. All the patients were addicted to alcohol for 8 - 10 years. Of the 50 patients enrolled, 39 of them completed the 8 weeks program including complete abstinence from alcohol during this period. Fasting blood samples were collected on admission and again after 8 weeks of alcohol abstinence for analyses of serum homocysteine and serum prealbumin, transferrin, total proteins and albumin, gammaglutamyl transferase (GGT) and alanine transaminase (ALT). Of the 50 patients enrolled in the study, 39 completed the 8 weeks rehabilitation program. 11 patients discontinued within 2 weeks of admission. During the 8 weeks of complete alcohol abstinence, patients were given a balanced diet and multivitamin supplements. A significant improvement in their nutritional status was noted by the elevation of serum levels of prealbumin, transferrin, total proteins and albumin. Serum homocysteine levels decreased significantly (p<0.002) to normal levels from previous hyperhomocytenemia. This was accompanied by decrease in serum GGT and ALT levels indicating improved liver functions. Serum estimation of homocysteine in chronic alcoholics is important to assess whether the patient will have a successful rehabilitation. Normal homocysteine levels are achieved after dietary changes and abstinence from alcohol. Timely correction of hyperhomocysteinemia also provides successful rehabilitation.
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PMID:Association of hyperhomocysteinemia to alcohol withdrawal in chronic alcoholics. 2310 41

Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level.
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PMID:Impact of Dyrk1A level on alcohol metabolism. 2721 78

Hyperhomocysteinemia, defined by an increased plasma homocysteine level, is commonly associated with chronic liver diseases. A link between the elevated homocysteine level and oxidative stress has been demonstrated. Indeed the pathogenesis of liver diseases in the case of hyperhomocysteinemia could be due to this production of oxidative stress. Many studies have demonstrated the antioxidative properties of lycopene, a carotenoid. Therefore, the present study was designed to induce hyperhomocysteinemia in male Wistar rats in order to analyze the effect of lycopene supplementation on homocysteine metabolism, on phase I and phase II xenobiotic-metabolizing enzyme activities, and on liver injury by histological examination and analysis of biochemical markers. We found that rats with a high methionine diet showed abnormal histological features, with an increase of serum homocysteine, alanine aminotransferase and aspartate aminotransferase levels, decreased hepatic cystathionine beta synthase and S-adenosyl-homocysteine hydrolase activities and an increased hepatic malondialdehyde level. We demonstrated the reversal effect of lycopene supplementation on hyperhomocysteinemia. Taken together, these findings provide additional clues on the hepatoprotective effects of lycopene.
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PMID:Hepatoprotective effects of lycopene on liver enzymes involved in methionine and xenobiotic metabolism in hyperhomocysteinemic rats. 2723 43


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