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)

Adefovir dipivoxil, a nucleotide analog of adenosine monophosphate, is an antiviral agent that suppresses hepatitis B virus (HBV) replication through inhibition of DNA polymerase and by chain termination. To determine the effectiveness of adefovir, three populations of patients with chronic hepatitis B patients were studied: hepatitis B e antigen (HBeAg)-positive patients, HBeAg-negative patients, and patients with lamivudine-resistant tyrosine-methionine-asparate-aspartate (YMDD) mutants. All three groups of patients were treated for 48 weeks with adefovir 10 mg/d, and significant reduction in serum HBV DNA and normalization of serum alanine aminotransferase (ALT) were noted. Significant improvement in liver histology was noted in HBeAg-positive and in HBeAg-negative patients. Significant HBeAg loss and HBeAg seroconversion rates were noted in HBeAg-positive patients and in lamivudine-resistant patients. No major drug-related side effects were noted. Adefovir 10 mg/d orally is safe and effective for treatment of chronic hepatitis B.
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PMID:Treatment of patients with chronic hepatitis B with adefovir dipivoxil. 1519

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. Leptin-deficient obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum alanine aminotransferase levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-alpha, TGF-beta, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.
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PMID:Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. 1525 62

In alcoholic steatohepatitis, hepatic microvascular changes have pathogenic significance for hepatocellular function, perisinusoidal fibrosis, and portal hypertension. It is unclear whether similar changes occur in other forms of steatohepatitis. We therefore examined whether hepatic microvascular dysfunction occurs in fibrosing steatohepatitis induced by feeding mice a high-fat methionine- and choline-deficient (MCD) diet. Using in vivo microscopic--as well as histological and electron microscopic--methods, together with measurements of alanine aminotransferase (ALT), lipid content, and oxidative stress, hepatic microvascular structure and function were studied in relation to inflammatory and fibrotic changes during evolution of steatohepatitis. At 3 weeks of MCD diet intake, serum ALT was elevated and hepatic steatosis was pronounced. By 5 weeks, necroinflammatory change was noteworthy, and by 8 weeks perisinusoidal fibrosis was established. Compared with mice receiving the high-fat diet supplemented with methionine and choline (controls), levels of hepatic lipid and lipoperoxides were elevated at 3 weeks and beyond. The numbers of perfused sinusoids were significantly reduced at each time point. Enlarged, fat-laden hepatocytes together with perivascular fibrosis narrowed sinusoidal lumens, making vessels tortuous and impairing sinusoidal perfusion. At 3 and 5 weeks, MCD diet caused significant increases in phagocytic activity of macrophages in centrilobular regions. By 8 weeks, macrophage activity was less striking, but the number of leukocytes adherent to the sinusoidal lining had increased 5-fold compared with controls. In conclusion, these results are consistent with a dysfunctional hepatic microvasculature. Thus, microvascular changes may contribute to progressive liver injury in metabolic and toxic forms of steatohepatitis.
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PMID:Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice. 1536 43

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

Pathogenesis of steatohepatitis, a common liver disease, remains controversial. It is proposed that fatty liver with a second hit capable of inducing necroinflammation results in nonalcoholic steatohepatitis. Long chain and very long chain fatty acids are considered important in induction of steatohepatitis. Peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in beta-oxidation of long chain and very long chain fatty acids and mitogenic effect caused by peroxisome proliferators in the liver. To determine the role of PPARalpha in the pathogenesis of steatohepatitis and compensatory liver cell hyperplasia, we have used PPARalpha null mice and methionine and choline deficient nutritional model. Male and female PPARalpha null mice and wild type mice were fed methionine and choline deficient diet (MCDD) or normal chow for 4 weeks. Livers were analyzed morphologically for steatosis, steatohepatitis and hepatocyte proliferation (PCNA labeling) and biochemically for triglyceride levels. In addition, serum alanine transaminase, aspartate transaminase and triglyceride levels were measured. In MCDD fed PPARalpha null mice there was severe steatohepatitis and very high liver triglyceride levels compared to wild type mice. Serum aspartate transaminase levels were also significantly higher in MCDD fed PPARalpha null mice compared to wild type mice. The severity of steatohepatitis in MCDD fed male and female PPARalpha null mice was greater compared to wild type mice fed the same diet. The PCNA labeling index was similar in PPARalpha null mice and wild type mice fed MCDD, and significantly higher in both the groups compared to the mice fed control diet. These findings indicate that defective fatty acid oxidation aggravates steatohepatitis caused by methionine and choline deficiency and further establishes the role of long chain and very long chain fatty acids in the pathogenesis of steatohepatitis. In addition, the results of this study also indicate that there is no difference between males and females in the severity of steatohepatitis induced by MCDD and lack of PPARalpha does not affect compensatory hyperplasia in the liver.
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PMID:Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis. 1551 75

Choline deficiency and treatment with methotrexate (MTX) both are associated with fatty infiltration of the liver. Choline, methionine, and folate metabolism are interrelated and converge at the regeneration of methionine from homocysteine. MTX perturbs folate metabolism, and it is possible that it also influences choline metabolism. We fed rats a choline deficient diet for 2 weeks and/or treated them with methotrexate (MTX; 0.1 mg/kg daily). Choline deficiency lowered hepatic concentrations of choline (to 43% control), phosphocholine (PCho; to 18% control), glycerophosphocholine (GroPCho; to 46% control), betaine (to 30% control), phosphatidylcholine (PtdCho; to 62% control), methionine (to 80% control), and S-adenosylmethionine (AdoMet; to 57% control), while S-adenosylhomocysteine (AdoHcy) and triacylglycerol concentrations increased (to 126% and 319% control, respectively). MTX treatment alone lowered hepatic concentrations of PCho (to 48% control), GroPCho (to 69% control), betaine (to 55% control), and AdoMet (to 75% control). The addition of MTX treatment to choline deficiency resulted in a larger decrease in AdoMet concentrations (to 75% control) and larger increases in AdoHcy and triacylglycerol concentrations (to 150% and 500% control, respectively) than was observed in choline deficiency alone. Livers from MTX-treated animals used radiolabeled choline to make the same metabolites as did livers from controls (most of the label was converted to PCho and betaine). In choline deficient animals, most of the labeled choline was converted to PtdCho. Therefore, MTX depleted hepatic PCho, GroPCho, and betaine by a mechanism that was different from that of choline deficiency. MTX increased the extent of fatty infiltration of the liver in choline deficient rats, and choline deficiency and MTX treatment damaged hepatocytes as measured by leakage of alanine aminotransferase activity. Our data are consistent with the hypothesis that the fatty infiltration of the liver associated with MTX treatment occurs because of a disturbance in choline metabolism.
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PMID:Effects of choline deficiency and methotrexate treatment upon rat liver. 1553 71

Current strategies for treating hepatitis B focus on clearance of active HBV infection through suppression of viral replication by interferon-alpha (IFN-alpha) and the nucleoside analogs (lamivudine and adefovir). Lamivudine therapy for 1 year leads to HBeAg seroconversion in 16-18% of patients compared to 4-6% of untreated controls, to histological improvement in 49-56% treated patients and in 23-25% controls. HBeAg seroconversion rates increase with the duration of lamivudine therapy from 17% at 1 year to 27, 40, 47 and 50% at 2, 3, 4 and 5 years, respectively. When prescribing lamivudine, drug resistance due to the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations that increases with duration of therapy and the potential risk of a severe flare of hepatitis with sudden cessation of therapy, probably greatest in patients with cirrhosis, are realistic concerns. After 48 weeks of treatment with 10 or 30 mg of adefovir dipivoxil per day, significantly more patients with HBeAg-positive chronic hepatitis B than those on placebo had histologic improvement (53, 59 and 25%, respectively), a reduction in serum HBV DNA levels (by a median of 3.52, 4.76 and 0.55 log copies/ml), undetectable levels of serum HBV DNA (21, 39 and 0%), normalisation of ALT levels (48, 55 and 16%) and HBeAg seroconversion (12, 14 and 6%). In HBeAg negative patients treated with adefovir dipivoxil (10mg/day) for 48 weeks, ALT levels had normalised in 72% (29% in the placebo group), serum HBV DNA levels were reduced to fewer than 400 copies/ml in 51% (none in the placebo group), liver histology improved in 64% (33% in the placebo group). No adefovir-associated resistance mutations of viral DNA were detected. Ongoing studies investigate combination therapy with lamivudine or IFN.
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PMID:Treatment of chronic viral hepatitis. 1558 3

One hundred and thirty-one post-liver transplantation patients with chronic hepatitis B and failing lamivudine therapy with detectable serum hepatitis B virus (HBV) deoxyribonucleic acid by hybridization assays or > or =1 x 10(6) copies/mL by polymerase chain reaction, and elevated alanine transaminase levels despite continuous lamivudine, were enrolled in an open-label study of adefovir dipivoxil. The B and C domains of HBV polymerase were sequenced for baseline samples to determine the presence of lamivudine resistance mutations. The results showed that 98% of the samples had tyrosine-methionine-aspartate-aspartate (YMDD) mutations, indicating a strong correlation between the above clinical definition of lamivudine treatment failure and the presence of YMDD mutations. In addition to the rtM204V/I and the rtL180M mutations, the mutation rtV173L was identified in 19% of patients. Four major patterns of lamivudine-resistant HBV were identified: rtL180M + rtM204V (60%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%) and rtL180M + rtM204I (9%). Treatment with adefovir dipivoxil showed similar antiviral efficacy in patients with lamivudine-resistant virus from all four patterns.
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PMID:Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients. 1565 50

Telbivudine, the prototype member of beta-L-2 -deoxynucleosides, has proven to be safe in in vitro animal and human studies. Telbivudine given for 4 weeks resulted in an 8-log reduction of woodchuck hepatitis virus DNA, and a 3.8-log reduction of hepatitis B virus DNA in human. After 52 weeks of telbivudine treatment there was an approximate 6-log reduction of hepatitis B virus DNA levels, hepatitis B virus DNA became undetectable by PCR assay in 61% of patients. Its antiviral efficacy is significantly better than lamivudine. The probability of tyrosine-methionine-aspartate-aspartate mutations at 52 weeks of telbivudine therapy is low, although still occurring in 4.5% of patients. After 96 weeks of therapy, the proportion of patients with undetectable hepatitis B virus DNA by PCR assay increased to 71%, but genotypic resistance also increased to 18.2%, with only 4.5% showing alanine aminotransferase flares. Telbivudine is probably one of the most potent antiviral agents for hepatitis B virus that will become available in the near future.
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PMID:Telbivudine: an upcoming agent for chronic hepatitis B. 1610 94

Toll-like receptors (TLR) recognize pathogen-derived molecules and induce downstream activation of inflammatory pathways. Fatty liver has been shown to result in increased sensitivity to lipopolysaccharide (LPS), a TLR4 ligand. In this study, we investigated the roles of TLR2 and TLR4 in liver damage and on cytokine induction in a methionine-choline deficient (MCD) diet-induced model of nonalcoholic steatohepatitis. We found that mice with nonalcoholic fatty liver had increased liver injury and inflammatory cytokine induction after challenge with a TLR4 but not with a TLR2 ligand. TLR2 deficient mice were not protected against the development of steatohepatitis after MCD diet feeding. On the contrary, TLR2 mice had significantly higher levels of serum ALT and greater TNF-alpha levels after LPS challenge suggesting increased liver injury. This was associated with reduced production of IL-6, a cytokine with hepatoprotective effects in fatty liver. Increased liver injury in the MCD diet-fed TLR2 mice was associated with reduced baseline and LPS-induced NF-kB and PPRE binding compared to MCS controls. These results demonstrate that TLR2 deficiency results in increased liver injury in association with nonalcoholic steatohepatitis and may suggest a protective role for TLR2-mediated signals in liver injury.
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PMID:Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. 1634 99


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