Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 3-month-old girl presented with anorexia, failure to thrive and drowsiness. She was mildly icteric with hepatomegaly and peripheral oedema. Disordered liver function tests were associated with the biopsy appearances of a giant cell hepatitis and with a Fanconi syndrome. At the age of 16 weeks she collapsed with profound hypoglycaemia. Fasting also provoked hypoglycaemia with lactic acidaemia. She became increasingly irritable and hypotonic and, although initially liver and renal function improved, she deteriorated and died of hepatocellular failure and septicaemia. A post-mortem revealed massive fatty degeneration of the liver. The activity of phosphoenolpyruvate carboxykinase in her cultured skin fibroblasts was 16% of controls. Her brother died at the age of 4 weeks of sudden infant death syndrome.
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PMID:Mitochondrial phosphoenolpyruvate carboxykinase deficiency. 308 95

Male mice were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by gavage. C57BL/6J (C57) mice received 0.03 to 235 micrograms/kg, DBA/2J (DBA) mice 1 to 3295 micrograms/kg. On Day 8 after dosing blood was collected, and livers and kidneys were removed. Body weights and feed intake were not much affected until Day 8 after exposure. Hepatomegaly developed at doses above 3 and 97.5 micrograms/kg in C57 and DBA mice, respectively. Ethoxyresorufin O-deethylase activity was induced in liver with an ED50 of 1.1 and 16 micrograms/kg and in kidney with an ED50 of 65 and 380 micrograms/kg in C57 and DBA mice, respectively. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in livers of both mouse strains was reduced over the entire dose range, displaying a plateau in the dose response at the onset of acute toxicity of TCDD. This enzyme activity was decreased by as much as 80% at the respective lethal doses. PEPCK activity in kidney was not affected. Glucose-6-phosphatase activity (G-6-Pase) in liver was altered only in the lethal dose range with a maximum reduction of about 50%. Serum glucose concentration was reduced over the entire dose range, but the reduction was significant only at doses in which G-6-Pase activity was affected, reaching levels as low as 3 mmol/liter in DBA mice. Tryptophan 2,3-dioxygenase activity was not lowered at any dose of TCDD in either mouse strain, and no increase in serum tryptophan levels was observed. Serum levels of thyroxine (T4) and triiodothyronine (T3) were dose dependently decreased over most of the dose range administered, with T3 levels exactly paralleling T4 levels in both mouse strains. It is concluded that TCDD causes acute toxicity in male C57 and DBA mice by a severe reduction of gluconeogenesis, but, in contrast to rats, it does not affect tryptophan homeostasis. Following administration of TCDD serum T3 levels in the mouse appear to correlate with T4 levels, whereas in the rat they are independent of each other.
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PMID:Correlation between toxicity and effects on intermediary metabolism in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male C57BL/6J and DBA/2J mice. 787 71

Mice expressing SV40 T-Antigen in liver under control of the phosphoenolpyruvate carboxykinase promoter were generated. By altering the carbohydrate content of the diet, TAg expression, the rate of hepatocyte proliferation and apoptosis, and hence hepatocarcinogenesis, could be regulated. Carbohydrate-mediated suppression of TAg resulted in slow hepatic growth that progressed to focal hepatocellular carcinoma (HCC) after a long latency period. In contrast, induction of TAg by feeding mice a low carbohydrate diet resulted in massive hepatomegaly that progressed rapidly to diffuse multifocal HCC. Hepatic TAg expression could be efficiently repressed by switching mice from the low to the high-carbohydrate diet, which if instigated prior to the development of HCC, resulted in rapid regression through a p53-independent reduction in hepatocyte proliferation and an increase in hepatocyte apoptosis. Although liver growth was accompanied by compensatory hepatocyte apoptosis, an apoptotic deficit developed following chronic exposure to high levels of TAg. This was associated with Akt phosphorylation and increased expression of the antiapoptotic molecules bfl-1/A1, TIAP, and A20. Mice were resistant to Fas-induced hepatocellular apoptosis due to severely impaired caspase activation and failed activation of the mitochondrial amplification loop. This model will be useful to investigate oncogene-mediated disruption of the cell cycle and apoptosis, and to determine which processes constitute fixed, or reversible aspects of the tumorigenic process.
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PMID:Induction of hepatocyte proliferation and death by modulation of T-Antigen expression. 1271 28

Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH(2)-terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phospho-fructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myr-Akt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1.
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PMID:Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. 1463 50

High-sucrose and high-fat diets induce deregulation in the metabolism of lipids and carbohydrates. This study aimed to detect the initial consequences on lipogenesis, gluconeogenesis and insulin signaling in the livers of rodents fed high-fat and/or high-sucrose diets for a short period of time. Male mice received a standard chow (SC), high-fat (HF), high-sucrose (HSu) or high-fat, high-sucrose (HFHSu) diet for 4 weeks. At euthanasia, blood was collected and the liver was removed for histomorphometrical and molecular analysis. The HF, HSu and HFHSu groups presented glucose intolerance, hepatomegaly, liver steatosis and lipid profile alteration when compared to the SC group (p < 0.0005). Additionally, there was an elevation in protein levels involved in lipogenesis (SREBP-1c), gluconeogenesis (PEPCK and G6Pase) and insulin signaling (IRS-1 and Akt) in the livers from the experimental groups compared to the SC group (p < 0.0005). Thus, we conclude that a short-term HF and/or HSu diet promotes glucose intolerance and liver damage in adult male mice. Surprisingly, the short exposure to excess sucrose in the diet promoted glucose intolerance and liver damage even in the absence of an increase in body mass or changes in serum insulin, cholesterol and triacylglycerol levels.
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PMID:Short Exposure to a High-Sucrose Diet and the First 'Hit' of Nonalcoholic Fatty Liver Disease in Mice. 2731 25

Mitogen inducible gene-6 (Mig-6) is a feedback inhibitor of epidermal growth factor receptor (EGFR) signaling pathway. The liver-specific knockout mice of the Mig-6 gene (Mig-6 d/d ) showed hepatomegaly and increased hypercholesterolemia. In this study, the biomarkers of insulin resistance and the effects of high-fat diets in the wild (Mig-6 f/f ) and Mig-6 d/d mice were analyzed. The fasting plasma concentrations of glucose, triglyceride, cholesterols, free fatty acids, and HOMA-IR were measured and the glucose tolerance and insulin resistance tests were performed in the 25-week-old Mig-6 f/f and the Mig-6 d/d mice. The protein levels of active insulin receptor, glucose 6-phosphatase, and phosphoenolpyruvate carboxykinase were analyzed in the liver and fat. The fasting plasma cholesterol and glucose concentration were higher in the Mig-6 d/d mice than the Mig-6 f/f mice with increased fat deposition in the liver. But the Mig-6 d/d mice had the improved glucose intolerance and insulin resistance without increased amount of phosphoinsulin receptor after insulin infusion in the liver. The hepatic concentration of phosphoenolpyruvate carboxykinase was increased in fasting Mig-6 d/d mice. The feeding of high-fat diet accelerated the plasma lipids profiles and HOMA-IR in the Mig-6 d/d mice but had no differential effects in oral glucose tolerance test and insulin tolerance test in both genotypes. These results suggest that the activated EGFR signaling might increase the fasting plasma glucose concentration through inducing the hepatic steatosis and the improved whole-body insulin resistance in the KO mice be caused by decreased adipogenesis in fat tissues.
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PMID:Fatty Liver and Insulin Resistance in the Liver-Specific Knockout Mice of Mitogen Inducible Gene-6. 2805 90