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

The activity of acetyl-CoA carboxylase (ACC), a rate-limiting enzyme of fatty acid biosynthesis and malonyl-CoA production, can be regulated by several mechanisms, including multisite covalent phosphorylation, both in vitro and in intact cells. Evidence has been presented by others to indicate that a 5'-AMP-activated protein kinase (AMPK) is likely the major regulatory kinase active on ACC. While insulin is known to activate ACC in several cell types, accompanied by changes in ACC phosphorylation, the mechanism underlying this activation has been obscure. In the present study, we have examined, in Fao hepatoma cells, the effects of insulin on ACC and AMPK activity, the latter measured with a synthetic peptide corresponding to one of the phosphorylation sites on ACC for AMPK. Our results show that insulin leads to inhibition of kinase activity prior to the onset of ACC activation; the peak of maximal kinase inhibition (approximately 35% at 10 min) is seen to precede the onset of ACC activation (20 min). The inhibition of kinase activity due to insulin is observed both in the absence and presence of varying stimulating concentrations of added 5'-AMP. Both kinase inhibition and ACC activation display similar insulin sensitivity (A50 0.3 nM). Preservation of this insulin-induced kinase inhibition requires the presence of protein phosphatase inhibitors in the cell lysis buffer, suggesting that AMPK itself might be regulated by insulin-stimulated changes in kinase phosphorylation. Taken together, these data are consistent with the hypothesis that the 5'-AMP-activated protein kinase is a regulated component of the insulin signal transduction pathway and may be the major target for insulin regulation of ACC.
 ...
PMID:Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5'-AMP-activated protein kinase. 134 11

Acetyl-CoA carboxylase (ACC) can be regulated in vitro via phosphorylation by a 5'-AMP-activated protein kinase. A potential intracellular role for this kinase has been studied in the Fao hepatoma cell by manipulating the intracellular adenine nucleotide pool with ATP-depleting agents. Three different ATP depletors, antimycin A, dinitrophenol, and sodium azide, all promote the rapid loss of ACC activity characterized by a marked reduction in enzyme Vmax, abolition of citrate-independent activity, an increase in the Ka for citrate and a reduction in the mass of a complex between the two major ACC isozymes. These effects persist through enzyme purification on monomeric avidin-Sepharose and are accompanied by an increase in 32P-content, both consistent with depletor-induced covalent enzyme modification. The effects of ATP depletors in intact cells are mimicked in vitro on phosphorylation of ACC by the 5'-AMP-activated protein kinase and are reversible on dephosphorylation. These data indicate that ACC activity is sensitive to the intracellular adenylate charge, but that changes in the state of enzyme phosphorylation, rather than direct allosteric regulation by adenine nucleotides, underly this mode of enzyme control. This kinase-mediated modulation provides a mechanism for altering the rate of fatty acid synthesis and, secondarily, fatty acid oxidation, depending on the rate of ATP generation from carbohydrate-derived precursors in several tissues in vivo.
 ...
PMID:Regulation of intracellular acetyl-CoA carboxylase by ATP depletors mimics the action of the 5'-AMP-activated protein kinase. 168 96

5-Amino-4-imidazolecarboxamide riboside (AICAR) is known to stimulate rat liver 5'-AMP-activated protein kinase (AMPK). AMPK is the mammalian homologue of Snf1p in yeast, involved in derepression of glucose-repressed genes. We used AICAR to test if AMPK could also play a role in the regulation of glucose-dependent genes in mammalian cells. At a concentration which induces phosphorylation-dependent inactivation of HMG-CoA reductase, AICAR blocked glucose activation of three glucose responsive genes, namely L-type pyruvate kinase (L-PK), Spot 14 and fatty acid synthase genes in primary cultured hepatocytes, but was without any action on glucose phosphorylation to glucose 6-phosphate and on expression of PEPCK, albumin and beta-actin genes. AICAR was also found to inhibit activation of the L-PK gene promoter by glucose in transiently transfected hepatoma cells. Therefore our results suggest that AMPK is probably involved in the glucose signal pathway regulating gene expression in the liver.
 ...
PMID:The 5'-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex. 970 98

Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or beta-actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes.
 ...
PMID:5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. 1086 40

Insulin-like growth factor-binding protein-1 (IGFBP-1) is stimulated during intensive exercise and in catabolic conditions to very high concentrations, which are not completely explained by known regulators such as insulin and glucocorticoids. The role of AMP-activated protein kinase (AMPK), an important signaling system in lipid and carbohydrate metabolism, in regulating IGFBP-1 was studied in H4-II-E rat hepatoma cells. Arsenic(III) oxide and 5-aminoimidazole-4-carboxamide-riboside (AICAR) were used as activators. AICAR (150 microM) stimulated IGFBP-1 secretion twofold during a 5-h incubation (P = 0.002). Insulin (100 ng/ml) inhibited IGFBP-1 by 80% (P < 0.001), but this was completely abolished in the presence of 150 microM AICAR. The effect of dexamethasone in stimulating IGFBP-1 threefold was additive to the effect of AICAR (P < 0.001) and, in the presence of AICAR, was incompletely inhibited by insulin. In conclusion AMPK is identified as a novel regulatory pathway for IGFBP-1, stimulating secretion and blocking the inhibitory effect of insulin.
 ...
PMID:Stimulation of IGF-binding protein-1 secretion by AMP-activated protein kinase. 1130 32

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates IGF availability for glucose homeostasis. The IGFBP-1 promoter shares common regulatory response elements with phosphoenol pyruvate carboxykinase (PEPCK), the expression and activity of which is inhibited by lithium chloride, associated with an inhibition of glycogen synthase kinase (GSK)-3 activity, in the rat hepatoma cell line H4-II-E. We therefore determined the effect of lithium chloride on IGFBP-1 expression and secretion in H4-II-E cells. Lithium chloride inhibited IGFBP-1 secretion in a dose response and reversible manner by approx 80% during 5-h and 16-h incubations. An inhibitory effect on IGFBP-1 mRNA expression was observed at 2 h. The inhibitory effect of lithium and insulin were not additive when used alone, but inhibition by lithium occurred when insulin action was blocked by activating AMP-activated protein kinase with 5-aminoimidazole-4-carboxamide-riboside (AICAR). These findings suggest that GSK-3 inhibition, or another pathway activated by lithium, may be involved in a pathway controlling IGFBP-1, inhibiting synthesis when insulin activity is absent or impaired.
 ...
PMID:Lithium chloride inhibits the expression and secretion of insulin-like growth factor-binding protein-1. 1173 24

Expression of the catalytic subunit of glucose-6-phosphatase (G6Pase) has recently been shown to be transactivated by the transcription factor FKHR. Insulin and conditions of energy depletion are known repressors of the G6Pase gene. Whereas insulin is known to inhibit G6Pase expression by phosphorylation and nuclear exclusion of FKHR, the mechanism of repression of G6Pase by energy depletion is unknown. Here, we have studied the effect of glucose starvation and AICAR, an activator of AMP-activated protein kinase (AMPK) on G6Pase expression and the expressional level of FKHR-protein in hepatic cells. Using a H4-hepatoma cell line stably overexpressing FKHR, we found that both glucose starvation and treatment of cells with AICAR strongly repressed G6Pase expression and led to an almost complete disappearance of the FKHR protein, whereas the levels of control proteins and FKHR mRNA were not affected. Our data suggest that AICAR and glucose starvation inhibit G6Pase expression by a reduction of the cellular level of FKHR, presumably mediated by specific degradation of the protein.
 ...
PMID:Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. 1213 May 86

The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the alpha subunit of AMPK in a dose- and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviral-mediated expression of a constitutively active AMPKalpha or a kinase-inactive AMPKalpha, respectively. An insulin-resistant state was induced by exposing cells to 30 mm glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3alpha/beta. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPKalpha. The kinase-inactive AMPKalpha increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPKalpha negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance.
 ...
PMID:AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. 1537 48

Phenobarbital (PB) administration is known to trigger pleiotropic responses, including liver hypertrophy, tumor promotion, and induction of genes encoding drug-metabolizing enzymes. The induction of human CYP2B6 and the rat (CYP2B1) and mouse (Cyp2b10) homologues by PB is mediated by the nuclear receptor constitutive androstane receptor (CAR). The study of CYP2B gene regulation and CAR activity by PB has been difficult due to the lack of a cellular model. In this study, we describe a novel differentiated human hepatoma cell line (WGA), derived from HepG2, which expresses CYP2B6 and CAR. WGA cells represent a powerful system to study the regulation of CYP2B6 gene expression by PB. There is evidence that CAR activity is regulated by phosphorylation and that regulation of some CYP genes depends on the nutritional status of cells. The AMP-activated protein kinase (AMPK) functions as an energy sensor and is activated when cells experience energy-depleting stresses. In this report, we show that addition of 5-amino-imidazole carboxamide riboside, an AMPK activator, to WGA and human hepatocytes induces CYP2B6 gene expression. Expression of a constitutively active form of AMPK mimics the PB induction of CYP2B6 and CYP2B1 gene expression. Conversely, the expression of a dominant negative form of AMPK inhibits the induction of these genes by PB. Finally, we demonstrate, for the first time, that AMPK activity increases in cells cultured with PB. Our data strongly support a role for AMPK in the PB induction of CYP2B gene expression and provide new insights into the regulation of gene expression by barbiturate drugs.
 ...
PMID:AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line. 1557 72

Alcoholic fatty liver is the earliest and most common response of the liver to alcohol in heavy alcohol use, and it may be a precursor of more severe forms of liver injury. We and colleagues in our laboratory found that in two rat hepatoma cell lines, H4IIEC3 and McA-RH7777, ethanol markedly induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter through increased levels of mature SREBP-1 protein. Whereas inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells, supporting the idea that the effect is likely mediated by acetaldehyde. Consistent with these in vitro findings, consumption of a low-fat diet with ethanol by mice for 4 weeks resulted in a significant increase in the abundance of the mature (active) form of hepatic SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of lipogenic genes as well as the accumulation of triglyceride in the livers. Taken together, these findings seem to indicate that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver. We and colleagues in our laboratory further studied the mechanisms of ethanol activation of SREBP-1 by identifying a new target of ethanol, adenosine 5'-monophosphate (AMP)-activated protein kinase. Our study results demonstrated that the effect of ethanol on SREBP-regulated promoter activation was mediated, at least in part, through inhibition of AMP-activated protein kinase. Consistent with this hypothesis, chronic ethanol feeding (4 weeks) resulted in a significantly reduced activity and protein level of AMP-activated protein kinase and increased acetyl coenzyme A carboxylase activity in the mouse livers.
 ...
PMID:Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. 1567 Jun 64


1 2 3 4 5 6 7 8 9 10 Next >>