Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin stimulates glucose transport in adipocytes via the rapid redistribution of the GLUT1 and GLUT4 glucose transporters from intracellular membrane compartments to the cell surface. Insulin sensitivity is dependent on the proper intracellular trafficking of the glucose transporters in the basal state. The bulk of insulin-sensitive transport in adipocytes appears to be due to the translocation of GLUT4, which is more efficiently sequestered inside the cell and is present in much greater abundance than GLUT1. The cell type and isoform specificity of GLUT4 intracellular targeting were investigated by examining the subcellular distribution of GLUT1 and GLUT4 in cell types that are refractory to the effect of insulin on glucose transport. Rat GLUT4 was expressed in 3T3-L1 fibroblasts and HepG2 hepatoma cells by DNA-mediated transfection. Transfected 3T3-L1 fibroblasts over-expressing human GLUT1 exhibited increased glucose transport, and laser confocal immunofluorescent imaging of GLUT1 in these cells indicated that the protein was concentrated in the plasma membrane. In contrast, 3T3-L1 fibroblasts expressing GLUT4 exhibited no increase in transport activity, and confocal imaging demonstrated that this protein was targeted almost exclusively to cytoplasmic compartments. 3T3-L1 fibroblasts expressing GLUT4 were unresponsive to insulin with respect to transport activity, and no change was observed in the subcellular distribution of the protein after insulin administration. Immunogold labeling of frozen ultrathin sections revealed that GLUT4 was concentrated in tubulo-vesicular elements of the trans-Golgi reticulum in these cells. Sucrose density gradient analysis of 3T3-L1 homogenates was consistent with the presence of GLUT1 and GLUT4 in discrete cytoplasmic compartments. Immunogold labeling of frozen thin sections of HepG2 cells indicated that endogenous GLUT1 was heavily concentrated in the plasma membrane. Sucrose density gradient analysis of homogenates of HepG2 cells expressing rat GLUT4 suggested that GLUT4 is targeted to an intracellular location in these cells. The density of the putative GLUT4-containing cytoplasmic membrane vesicles was very similar in HepG2 cells, 3T3-L1 fibroblasts, 3T3-L1 adipocytes, and rat adipocytes. These data indicate that the intracellular trafficking of GLUT4 is isoform specific. Additionally, these observations support the notion that GLUT4 is targeted to its proper intracellular locale even in cell types that do not exhibit insulin-responsive glucose transport, and suggest that the machinery that regulates the intracellular targeting of GLUT4 is distinct from the factors that regulate insulin-dependent recruitment to the cell surface.
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PMID:Intracellular targeting of the insulin-regulatable glucose transporter (GLUT4) is isoform specific and independent of cell type. 165 37

A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with insulin developed hepatoma. As the tumor grew, he lost his dependence on insulin therapy and experienced episodes of hypoglycemia. His response to infuse insulin was studied using the euglycemic clamp technique. Insulin was infused at rates of 1 and 10 mu/kg/min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 microU/ml, steady-state glucose consumption was 9.6 mg/kg/min, 50% more than in normals, and nearly three times greater than that in other cirrhotics. The insulin clearance rate was 4417 m1/m2/min, almost five and six times more than in normals and cirrhotics, respectively. Basal hepatic glucose production was 3.6 mg/kg/min, two and three times higher than in normal and in cirrhotic subjects, respectively. The decrease in amino acid during hyperinsulinemia was more than 30% higher than in normal and other cirrhotics. IFG-I and II levels were not elevated in this patient. Increased insulin sensitivity and increased insulin clearance and serum amino acid decrease in response to insulin in vivo, suggest that insulin responsive tissues are at last partially responsible for tumor hypoglycemia. The increased glucose disposal rate probably accounted for the disappearance of the diabetes.
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PMID:Case report: increased insulin sensitivity in tumor hypoglycemia in a diabetic patient: glucose metabolism in tumor hypoglycemia. 165 53

The insulin-receptor affinity of five human insulin analogues with one to four amino acid substitutions was measured with human hepatoma cells (HepG2). The binding affinities ranged from 0.05% for AspB25 insulin, 18% for AspB9, GluB27 insulin, 80% for AspB28 insulin, and 327% for AspB10 insulin to 687% for HisA8, HisB4, GluB10, HisB27 insulin relative to human insulin. Binding constants obtained by competition experiments at steady state with [125I]TyrA14-labeled insulin and unlabeled analogues and by kinetic studies with [125I]TyrA14-labeled analogues and insulin gave essentially the same values. The kinetic studies showed that differences in affinity between analogues were due to differences in both dissociation and association rate constants. The affinity for insulinlike growth factor I receptor was low, ranging from less than 0.005% for AspB25 insulin to 0.6% for HisA8, HisB4, GluB10, HisB27 insulin. The potencies of insulin analogues in activation of the tyrosine kinase of solubilized and partially purified insulin receptors from HepG2 cells, measured with the exogenous substrate poly(Glu80-Tyr20), ranked in the same order as the binding affinities, the actual values being somewhat elevated for the high-affinity analogues, however. We conclude that these human insulin analogues are active in insulin-receptor binding and tyrosine kinase stimulation but show wide variation in affinity.
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PMID:Receptor binding and tyrosine kinase activation by insulin analogues with extreme affinities studied in human hepatoma HepG2 cells. 165 69

The benign tumors hepatic adenoma and focal nodular hyperplasia are compared in their etiology, differential diagnosis, risk of transformation, and management. Hepatic adenomas range in size from 1-30 cm, averaged 8-10 cm in diameter, contain vacuoles and glycogen, but no Kupfer cells or bile ducts. Adenoma is usually symptomatic, causing pressure or hemorrhage. The risk of developing adenoma is increased with duration of oral contraceptive use, and chance of a larger tumor, a hemorrhage and mortality during pregnancy or surgery is also increased in pill users. Adenoma also occurs in people with Type Ia glycogen storage disease, and is associated with insulin-dependent diabetes. Often stopping oral contraceptives will cause an adenoma to regress. If not, It is best managed by elective resection, with 1% mortality, rather than 5-10% mortality due to spontaneous rupture. Adenomas can progress to adenomatosis, which are inoperable, or malignant transformation. Focal nodular hyperplasia is marked by a stellate scar, sometimes accompanied by hemangioma, but is asymptomatic. It is not increased in oral contraceptive users, but occurs in older women. It can transform to fibrolamellar hepatocellular carcinoma. The 2 benign lesions can be distinguished by radionuclide scanning and angiography. Only fine needle aspiration is advised for biopsy, because of the risk of hemorrhage with adenoma. Focal nodular hyperplasia takes up radionuclide, stains intensely on angiography, and is safe to biopsy percutaneously.
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PMID:Hepatic adenoma and focal nodular hyperplasia. 165 55

We conducted interviews on 74 patients with histologically confirmed hepatocellular carcinoma. These patients, aged 18-74 years, were black or white residents of Los Angeles County. We also interviewed 162 population control subjects who were comparable to the case patients by age, sex, and race. Cigarette smoking was a significant risk factor for hepatocellular carcinoma [relative risk (RR) = 2.1; 95% confidence limits (CL) = 1.1, 4.0]; the effects were similar in men and in women. Heavy alcohol consumption was another risk factor for hepatocellular carcinoma in men; men who consumed 80 g or more of ethanol per day had an RR of 4.7 (95% CL = 1.4, 15.4) relative to those who had never drunk alcohol on a weekly basis. The level of alcohol intake was relatively low in women, and no significant effect on risk of hepatocellular carcinoma was observed. Use of oral contraceptives was significantly related to risk of hepatocellular carcinoma in women (RR = 3.0; 95% CL = 1.0, 8.8); those who were exposed for more than 5 years exhibited a 5.5-fold increased risk (95% CL = 1.2, 24.8). The effects of these three risk factors on hepatocellular carcinoma development were independent of each other and independent of serologically determined viral hepatitis. Our data suggest that cigarette smoking, alcohol consumption, and use of oral contraceptives are major risk factors for hepatocellular carcinoma among non-Asian residents of Los Angeles County. We also observed a significant association between a history of diabetes and hepatocellular carcinoma (RR = 3.3; 95% CL = 1.5, 7.2), especially among those who had received insulin treatment (RR = 18.5; 95% CL = 2.2, 156.0). This association may have etiological significance.
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PMID:Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. 166 May 42

The present study investigates the effect of glucose on the gene expression of the hepatic glucoregulatory enzyme, phosphoenolpyruvate carboxykinase (PPrvck). By use of hepatocytes in culture and FAO hepatoma cells it could be demonstrated that glucose suppressed the effect of dibutyryl cyclic AMP (Bt2cAMP), glucocorticoids or both, to increase PPrvck mRNA and consequently PPrvck enzyme activity. Glucose had a dual effect; it reduced PPrvck gene transcription and it accelerated the rate of PPrvck mRNA degradation. The effect was specific for glucose, as glucose-related carbohydrates such as mannose, galactose and sorbitol were without effect on PPrvck mRNA. The repressive effect of glucose was limited to certain proteins; glucose had no effect on Bt2cAMP and glucocorticoid provoked induction of tyrosine aminotransferase (TAT). Also the pattern of mRNA in vitro translation products was virtually unaffected when FAO hepatoma cells were incubated either in the presence or absence of glucose, demonstrating the specificity of the effect of glucose on gene expression of selected proteins. In FAO hepatoma cells and in hepatocytes in culture, insulin, like glucose, also decreased PPrvck mRNA. While the effect of glucose and insulin was additive in FAO hepatoma cells, in primary hepatocytes in culture an effect of glucose by itself on PPrvck mRNA could only be demonstrated in the absence of insulin. Correspondingly also in vivo, the effect of glucose was demonstrated in the absence of insulin (provoked by streptozotocin diabetes); glucose application reduced the amount of hepatic PPrvck mRNA. To summarize, glucose is capable of suppressing the effect of glucocorticoids and Bt2cAMP on increasing the PPrvck mRNA level. The carbohydrate reduces the rate of PPrvck gene transcription and accelerates the rate of PPrvck mRNA degradation. While in FAO hepatoma cells the effect is evident in the presence of insulin, in hepatocytes in culture the effect of glucose cannot be demonstrated in the presence of insulin, questioning its role under physiological conditions.
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PMID:Transcriptional and post-transcriptional effects of glucose on liver phosphoenolpyruvate-carboxykinase gene expression. 166 21

Insulin stimulates RNA synthesis in the human hepatoma cell line J5. The mechanisms of insulin action on nuclear functions are not fully understood. To assess the possible action of nuclear insulin binding on RNA synthesis, we studied the insulin action by an in vitro transcription system using the nuclei isolated from control cells and insulin-stimulated J5 cells. Insulin binding was done by ligand binding assay. RNA synthesis was also studied in the nuclei treated with insulin in vitro. We found that a large pool of low-affinity binding sites existed in the isolated nuclei preparation without site-to-site interactions. These data suggest that the majority of nuclear insulin binding sites are located inside the nuclear envelope. Nuclear RNA synthesis was stimulated by the insulin (about a 4-fold increase when compared to the control) added to intact cells but not to isolated nuclei. We conclude that insulin stimulates nuclear RNA synthesis via interaction with plasma membrane receptors.
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PMID:Lack of binding effect of insulin on RNA synthesis to isolated nuclei. 167 2

Biochemical and morphological studies compared the ATP requirements for and the internalization routes of alpha 2-macroglobulin and insulin in H35 hepatoma cells. Cellular ATP concentrations were decreased more than 94% by 1 mM 2,4-dinitrophenol or 10 mM sodium azide, potassium cyanide, or oligomycin. ATP depletion decreased total cell-associated alpha 2-macroglobulin 70-90% by inhibiting binding 67-77% and receptor-mediated internalization 90-96%. Under the same conditions, insulin binding was decreased less than 10%, and endocytosis and intracellular accumulation were not affected. Quantitative electron microscopic analysis of the distribution of occupied receptors on the surface of control and treated cells was performed using colloidal gold-labeled alpha 2-macroglobulin or insulin. alpha 2-Macroglobulin concentrated in and was internalized almost exclusively by coated pits. Insulin was rarely associated with coated pits, but was found in and internalized by noncoated invaginations. ATP depletion did not affect receptor mobility or ligand-induced aggregation of either receptor. There was an increase in the amount of alpha 2-macroglobulin found in coated pit-like structures. The coat underlying pits in ATP-depleted cells was poorly defined and may account for the inability of coated pits to form and/or internalize. These results showed that receptor-mediated internalization via coated pits was ATP dependent, whereas internalization via pinocytotic invaginations was energy independent, which explained the difference in the ATP dependency of uptake for the two ligands. These observations suggested that autophosphorylation of the insulin receptor may not be involved in either the aggregation or internalization of the insulin-receptor complex, since ATP depletion did not affect either process. This study provided evidence that specialized mechanisms exist for the internalization of insulin which may be related to some of its intracellular effects.
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PMID:Differences in adenosine triphosphate dependency of receptor-mediated endocytosis of alpha 2-macroglobulin and insulin correlate with separate routes of ligand-receptor complex internalization. 168 53

Dietary factors are known to modulate concentrations of sex hormone-binding globulin (SHBG). In the present study we have investigated the possibility that insulin like growth factor-type I (IGF-I) may be an additional regulator of SHBG using cultured human hepatoma cells which secrete SHBG. The inhibitory effect of insulin on SHBG secretion by these cells was confirmed but, in addition, IGF-I was shown to inhibit SHBG secretion by about 40% at a concentration of 100 nmol/l. A similar degree of inhibition was achieved using insulin at a concentration of 10 mumol/l. Insulin, but not IGF-I, was also found to inhibit the secretion of a low molecular weight IGF-binding protein (IBP-I), which is also secreted by hepatoma cells. It is concluded that IGF-I is an additional regulator of SHBG secretion by these cells and that it may be involved in regulating SHBG secretion in vivo in response to dietary factors.
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PMID:Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells. 169 Feb 56

A human hepatoma cell line, HepG2, secretes a discrete insulin-like growth factor-binding protein (IGFBP-1) into serum-free medium, which is identical to the 25K mol wt BP in amniotic fluid and plasma. IGFBP-1 levels in vivo have been shown to be inversely correlated with circulating insulin concentrations. This study investigated the direct effects of insulin on IGFBP-1 production in vitro. Addition of insulin to HepG2 cultures induced a rapid dose-dependent decrease in IGFBP-1 synthesis and secretion independent of the glucose concentration in the medium. As assessed by ligand binding and specific RIA, levels of IGFBP-1 were 20-50% of control levels in 18-h conditioned medium from insulin-treated cells. Monoclonal antibody studies indicated that the suppressive effect of insulin on IGFBP-1 synthesis was mediated through specific interaction with the insulin receptor. Therefore, HepG2 cells respond to insulin by altering the synthesis and secretion of IGFBP-1 in a manner that mimics many of the changes in plasma IGFBP-1 levels observed in vivo and provide an in vitro model for studies of IGFBP-1 biosynthesis.
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PMID:Insulin regulation of insulin-like growth factor-binding protein production in cultured HepG2 cells. 169 Jul 45


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