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)

Adiponectin, secreted specifically from adipocytes, is thought to play a key role in the metabolic syndrome. Plasma adiponectin concentrations were studied in 36 typical nonalcoholic fatty liver (NAFL) women which is commonly associated with the metabolic syndrome. They were diagnosed as NAFL by ultrasound brightness, slightly elevated serum ALT levels and the exclusion of history of alcohol abuse and other known liver diseases. Compared with 64 control women, NAFL had a significant increase in the variables of the metabolic syndrome, other hepatic enzymes and leptin levels, while a reduction in AST/ALT ratio and adiponectin before (mean +/- SE: 7.2 +/- 0.5 vs 9.0 +/- 0.4 microg/ml, p < 0.005) and after adjustment for body fat mass (0.24 +/- 0.02 vs 0.34 +/- 0.02, p < 0.0001), atherogenic Index [(total cholesterol - HDLC)/HDLC: 3.2 +/- 0.3 vs 4.6 +/- 0.3, p < 0.005] or calculated insulin resistance (HOMA-R) (6.6 +/- 1.9 vs 8.6 +/- 0.9, p < 0.005). BMI and amylase were positive, and adiponectin/BMI was negative significant independent determinants of ALT value in multiple regression model. In conclusion, while hypoadiponectinemia was observed in NAFL, hypoadiponectinemia provides the possibility of fat accumulation in the liver.
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PMID:Plasma adiponectin decrease in women with nonalcoholic Fatty liver. 1564 78

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.
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PMID:Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. 1579 19

Currently used to treat severe acne, 13-cis-retinoic acid (13-cis-RA) is under investigation for its anticancer effects as is the isomer, all-trans-retinoic acid (all-trans-RA). Here, the effects of oral 13-cis-RA or all-trans-RA treatment on serum chemistry, leptin and adiponectin levels were evaluated. Adult Sprague-Dawley rats were gavaged once daily for 7 consecutive days with 13-cis-RA (7.5 or 15 mg kg(-1)), all-trans-RA (10 or 15 mg kg(-1)) (n=24/sex/dose), or soy oil (n=16/sex) and blood was sampled 30-480 min after the last gavage. The body weight was unaffected; however, the liver/body weight ratios were increased by both doses of all-trans-RA. Sex differences were noted for levels of cholesterol, creatine, triglycerides, albumin, alanine aminotransferase and total protein. Both doses of all-trans-RA reduced albumin levels to approximately 90% of the control and total protein levels to approximately 93% of the control while substantially elevating triglyceride levels to approximately 66%-99% above the control. Additionally, triglyceride levels of the 15 mg kg(-1) 13-cis RA group were approximately 62% higher than the controls and total protein levels were approximately 5% less. Glucose levels were affected by sex and RA treatment in that males treated with 15 mg kg(-1) of 13-cis-RA or 10 mg kg(-1) all-trans-RA had lower (13%-19%) levels than the same-sex controls; however, females were not similarly affected. Neither 13-cis-RA nor all-trans-RA treatment had significant effects on the levels of blood urea nitrogen, aspartate amino transferase, leptin or adiponectin. On a mg kg(-1) basis, all-trans-RA was more potent than 13-cis-RA. These results replicate previous findings of RA-induced increased triglyceride levels. Additionally, several new findings indicate there may be sex-specific effects of RA treatment. Finally, neither treatment appeared to alter the typical diurnal cycles of these endpoints.
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PMID:Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid. 1609 84

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 +/- 27 vs. 13 +/- 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNFalpha and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPARgamma, LXRalpha) was increased, whereas that of a lipolytic nuclear factor PPARalpha was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a. TNF type I receptor deficiency did not prevent obesity and SH. In conclusion, forced overfeeding with a high-fat diet in mice induces obesity, insulin resistance, and SH in the absence of TNF signaling or Cyp2e1 induction.
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PMID:Steatohepatitis induced by intragastric overfeeding in mice. 1617 2

Dietary factors promote obesity and obesity-related disorders, such as fatty liver disease. Natural killer T (NKT) cells are components of the innate immune system that regulate proinflammatory (Th-1) and anti-inflammatory (Th-2) immune responses. Previously, we noted that NKT cells are selectively reduced in the fatty livers of obese, leptin-deficient ob/ob mice and demonstrated that this promotes proinflammatory polarization of hepatic cytokine production, exacerbating lipopolysaccharide (LPS) liver injury in these animals. In the current study, we show that hepatic NKT cells are also depleted by diets that induce obesity and fatty livers in wild-type mice, promoting Th-1 polarization of hepatic cytokine production and sensitization to LPS liver injury despite persistent leptin. Adult male C57BL6 mice fed diets containing high amounts of either fat or sucrose, or combined high-fat, high-sucrose, develop increased hepatic NKT cell apoptosis and reduced liver NKT cells. The hepatic lymphocytes are more Th-1 polarized with increased intracellular interferon gamma and tumor necrosis factor alpha. Mice fed high-fat diets also exhibit more liver injury, reflected by 2-fold greater serum alanine aminotransferase (ALT) than control animals after receiving LPS. In conclusion, when otherwise normal mice are fed with high-fat or sucrose diet, they become obese, develop fatty livers, and acquire hepatic innate immune system abnormalities, including increased NKT cell apoptosis. The latter reduces liver NKT cell populations and promotes excessive hepatic production of Th-1 cytokines that promote hepatic inflammation. These diet-induced alterations in the hepatic innate immune system may contribute to obesity-related liver disease.
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PMID:Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. 1617 16

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.
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PMID:Defining the role of T cell-derived leptin in the modulation of hepatic or intestinal inflammation in mice. 1617 53

Several studies have reported an association between markers of liver injury, including elevated concentrations of alanine aminotransferase (ALT) aspartate aminotransferase (AST), and prospective risk of type 2 diabetes. We therefore examined the relationship between ALT and AST on the one hand, and serum adiponectin and highly sensitive CRP on the other, both of which have been reported to be associated with prospective risk of type 2 diabetes; we also tested for variable components of metabolic syndrome in 198 male college students aged 18-20 years. ALT showed a positive relationship with percentage body fat (r = 0.19, p = 0.02), serum leptin (r = 0.21, p = 0.01), LDL cholesterol (r = 0.29, p = 0.0003), triglyceride (r = 0.28, p = 0.0004) and apolipoprotein B (r = 0.35, p < 0.0001) even after adjustment for body mass index (BMI). Although there was a significant relationship with serum insulin, adiponectin (inversely), homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure, HDL cholesterol (inversely) and LDL particle diameter in simple regression analysis, significance disappeared after adjustment for BMI. In contrast, CRP (r = 0.16, p = 0.04) was associated with ALT after adjustment for BMI, although simple regression analysis revealed no association between the two. Relationships were smaller for AST, and significance disappeared after adjustment for BMI. Multiple regression analysis excluding lipid variables revealed significant and independent associations of ALT with adiponectin and percentage body fat. In a model including lipid variables, apolipoprotein B emerged as an independent predictor of ALT in addition to adiponectin and percentage body fat. These variables explained 29 % of ALT variability. In conclusion, serum ALT levels were associated with leptin and CRP as well as many components of the insulin resistance syndrome in young healthy men. Adiponectin, apolipoprotein B and percentage body fat emerged as significant and independent predictors of ALT. Since adiponectin and chronic subclinical inflammation have been reported to predict the development of type 2 diabetes and since abnormalities in apolipoprotein B metabolism occur in the early course of insulin resistance, these findings may be compatible with the association between liver markers and risk of diabetes.
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PMID:Serum alanine aminotransferase is associated with serum adiponectin, C-reactive protein and apolipoprotein B in young healthy men. 1652 13

The objectives of this research were to investigate the leptin levels among Chronic Hepatitis B Virus (HBV), Chronic Hepatitis C Virus (HCV) and non-alcoholic steatosis hepatitis (NASH) diseases of Thai patients compared with controls. Twenty of each HBV, HCV and NASH patients compared with sixty people as the control group from the Outpatient Department at the Hospital for Tropical Diseases, Bangkok, Thailand were investigated. Fasting blood samples were collected for investigation of leptin concentration, liver enzyme function tests and hematological variables. The serum leptin concentration of liver patients was significantly higher than that of control subjects. It might be due to the accumulations of fat cells in liver disease patients. However, there is no relationship between leptin level and other parameters such as BMI, ALT, AST, ALP and hematological variables. Liver enzyme functions levels are much higher in patients groups. White blood cells counts, platelets and hematocrit values are slightly lower in liver disease patients. Therefore, it is concluded that physiological regulation of leptin maintains in relation to body fat, even in chronic viral liver diseases. This finding and the apparent stage suggest the possibility that in the course of chronic viral diseases, serum leptin levels may reflect the extent of liver dysfunction.
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PMID:Serum leptin concentrations in chronic hepatitis. 1669 95

Hepatic injury elicits intracellular stress that leads to peroxidation of membrane lipids accompanied by alteration of structural and functional characteristics of the membrane, which affects the activity of membrane-bound ATPases. We have explored the effect of leptin on hepatic marker enzyme and membrane-bound adenosine triphosphatases in ethanol-induced liver toxicity in mice. The experimental groups were control, leptin (230 microg kg(-1), i.p. every alternate day for last 15 days), alcohol (6.32 g kg(-1), by intragastric intubation for 45 days), and alcohol plus leptin. Ethanol feeding to mice significantly (P < 0.05) elevated the plasma leptin, alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and hepatic lipid hydroperoxides (LOOH), and plasma and hepatic total ATPases, Na(+), K(+)-ATPase and Mg(2+)-ATPase. There was a significant decrease in Ca(2+)-ATPase and reduced glutathione (GSH). Leptin injections to ethanol-fed animals further elevated the levels of hepatic LOOH, plasma and hepatic total ATPases, Na(+), K(+)-ATPase and Mg(2+)-ATPase, while the Ca(2)-ATPase and GSH were decreased significantly. In addition, leptin administration was found to increase the plasma levels of leptin, ALT, ALP, GGT, Na(+) and inorganic phosphorous, and decrease the levels of K(+) and Ca(2+) in ethanol-fed mice. These findings were consistent with our histological observations, confirming that leptin enhanced liver ailments in ethanol-supplemented mice.
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PMID:Effect of leptin administration on membrane-bound adenosine triphosphatase activity in ethanol-induced experimental liver toxicity. 1687 59

Leptin-deficient ob/ob mice exhibit several metabolic and immune abnormalities, including thymus atrophy and markedly reduced inflammatory responses. We evaluated whether transplantation of wild-type (WT) white adipose tissue (WAT) into ob/ob mice could mimic the effect of recombinant leptin administration in normalizing metabolic, immune and inflammatory abnormalities. Female ob/ob mice received a subcutaneous transplantation of WAT obtained from WT littermates. A separate group of ob/ob mice was sham-operated. Despite raising leptin levels to only 15% of those observed in WT mice, WAT transplantation normalized metabolic abnormalities (glycemia, ALT, liver weight) in ob/ob mice and prevented further body weight gain. The transplanted group demonstrated normalization of thymus and spleen cellularity, thymocyte subpopulations and rates of thymocyte apoptosis. In the model of dextran sulfate sodium-induced colitis, WAT transplantation restored inflammation to levels equivalent to those of WT mice. Colonic production of IL-6 and MIP-2 was markedly reduced in the non-transplanted ob/ob group compared to transplanted ob/ob and WT mice. Our data indicate that WAT transplantation is an effective way to normalize metabolic as well as immune and inflammatory parameters in ob/ob mice. The threshold of leptin sufficient to normalize metabolic, immune and inflammatory function is significantly lower than levels present in lean WT mice. Finally, leptin derived exclusively from WAT is sufficient to normalize metabolic, immune and inflammatory parameters in ob/ob mice.
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PMID:Transplantation of wild-type white adipose tissue normalizes metabolic, immune and inflammatory alterations in leptin-deficient ob/ob mice. 1736 40


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