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:6.4.1.2 (acetyl-CoA carboxylase)
2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor (HGF)/scatter factor is known to be the most potent mitogen for hepatocytes. In this paper, we report that lipogenesis in primary cultured rat hepatocytes treated with 10 ng/ml of recombinant human HGF (rhHGF) for 24 h was stimulated, as measured by the incorporation of 3H2O into long-chain fatty acids, to more than twice as much as the control. Insulin (0.1 microM) was more effective than rhHGF but rhHGF did not show an additive or synergistic effect when added to insulin. We also showed that treatment with rhHGF increased the activities of glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme, key enzymes which supply NADPH for lipogenesis, and acetyl-CoA carboxylase, the rate-limiting enzyme of lipogenesis. The increase in G6PDH and acetyl-CoA carboxylase activities was accompanied by increases in the levels of mRNA for the enzymes. These results suggest that HGF is involved in liver regeneration not only by stimulation of cell proliferation but also by acceleration of differentiation of hepatocytes.
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PMID:Effect of hepatocyte growth factor/scatter factor on lipogenesis in adult rat hepatocytes in primary culture. 879 95

In pancreatic beta-cells, stimulation of insulin secretion by glucose and other nutrients requires metabolism of these nutrients to acetyl-CoA. Circumstantial evidence suggests that the conversion of acetyl-CoA to malonyl-CoA, which is a powerful inhibitor for carnitine palmitoyltransferase 1 and fatty acid oxidation, leads to insulin exocytosis, presumably by fatty acyl-CoA activation of certain ion channels. Since acetyl-CoA carboxylase (ACC) is the only enzyme which synthesizes malonyl-CoA, we generated transfectants of INS-1 cells which express antisense ACC mRNA in order to unequivocally establish that ACC is involved in glucose-induced insulin secretion. These cells showed lower ACC mRNA, protein and enzymatic activity than those of the control cells. Insulin secretion induced by nutrients such as glucose, amino acids, ketoisocaproate, and fatty acids was diminished commensurate with the level of ACC, while KCl induced insulin secretion was not affected.
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PMID:Acetyl-CoA carboxylase is essential for nutrient-induced insulin secretion. 895 60

The mechanisms by which triiodothyronine (T3), glucose, insulin, and glucagon regulate acetyl-CoA carboxylase expression in primary cultures of chick embryo hepatocytes have been investigated. Incubating hepatocytes with T3 in the absence of glucose caused a fourfold increase in acetyl-CoA carboxylase activity. Addition of glucose (20 mM) enhanced the T3-induced increase in acetyl-CoA carboxylase activity by threefold but had no effect on enzyme activity in the absence of T3. The effects of T3 and glucose on acetyl-CoA carboxylase activity were accompanied by similar changes in acetyl-CoA carboxylase mRNA levels, indicating that regulation occurred at a pretranslational step. Xylitol mimicked the effect of glucose on acetyl-CoA carboxylase mRNA abundance, suggesting that an intermediate(s) of the nonoxidative branch of the pentose phosphate pathway may be involved in mediating this response. Insulin accelerated the accumulation of acetyl-CoA carboxylase mRNA abundance caused by T3 and glucose but had no effect on steady-state levels of acetyl-CoA carboxylase mRNA in the absence or presence of T3. Glucagon caused a 65% decrease in the accumulation of acetyl-CoA carboxylase mRNA in hepatocytes incubated with T3 and glucose. The effects of T3, glucose, insulin, and glucagon on the abundance of acetyl-CoA carboxylase mRNA were accounted for by changes in the transcription rate of the acetyl-CoA carboxylase gene. These data support the hypothesis that T3, glucose, insulin, and glucagon play a role in mediating the effects of nutritional manipulation on transcription of acetyl-CoA carboxylase in liver.
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PMID:Triiodothyronine stimulates and glucagon inhibits transcription of the acetyl-CoA carboxylase gene in chick embryo hepatocytes: glucose and insulin amplify the effect of triiodothyronine. 901 9

Avian lipogenesis was studied in the chicken hepatocarcinoma LMH cell line. The differentiated and lipogenic status of these cells was evidenced by the presence of the albumin mRNA as well as of some mRNA coding for enzymes involved in lipogenesis (acetyl-CoA carboxylase, fatty acid synthase, delta 9 desaturase) and for apoproteins (apoprotein B and A1). These results were further confirmed by the analysis of triglyceride synthesis and secretion rates in growing cells. A time course analysis showed that triglyceride metabolism was affected by cell density. Hormone responsiveness of triglyceride production was also analyzed. Insulin, triiodothyronine and glucagon to a lesser extent were shown to regulate lipogenesis of LMH cells. The results were compared with those obtained in primary cultures of chicken hepatocytes.
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PMID:Triglyceride synthesis and secretion and lipogenesis implicated gene expression in the chicken hepatocarcinoma cell line LMH. 940 72

This study was designed to examine the role of insulin (INS) in regulating changes in lipid metabolism of larval and metamorphosing landlocked lamprey, Petromyzon marinus. Larvae and stage 6 metamorphosing individuals were injected intraperitoneally once per day for 2 days with either saline (0.6%), bovine INS (100 ng/g body weight), or alloxan (0.2 mg/g body weight). Insulin administration resulted in depressed plasma fatty acid (FA) levels, whereas alloxan injection elevated plasma FA levels at both life cycle intervals. In larvae, INS-induced hypolipidemia was attended by increased lipid concentration in kidney and muscle, reduced rates of lipolysis in kidney, liver, and muscle (as indicated by decreased triacylglycerol lipase activity), and, to a lesser extent, by higher rates of lipogenesis in kidney and muscle (as evidenced by higher acetyl-CoA carboxylase and/or diacylglycerol acyltransferase activities). In general, the effects of alloxan were opposite of those of INS. The alloxan-induced increase in plasma FA was supported by an enhanced rate of lipolysis in the kidney, a relatively lower rate of fatty acid synthesis in kidney, liver, and muscle, and a relatively lower renal rate of TG synthesis. In stage 6 metamorphosing lamprey, the INS-induced decline in plasma FA was attended by reduced renal and hepatic rates of lipolysis and by enhanced lipogenesis, as indicated by increased renal and hepatic rates of de novo fatty acid synthesis and hepatic and muscular rates of TG synthesis. In contrast, the increase in plasma FA induced by alloxan in stage 6 animals was supported by reduced TG synthesis in liver. Immunocytochemistry revealed that alloxan was not cytotoxic to pancreatic beta cells, suggesting that the effects of alloxan were extrapancreatic in the time frame of our study. Because insulin-induced lipogenesis and antilipolysis is similar to the pattern of lipid metabolism (phase I) displayed by lamprey during their spontaneous metamorphosis, INS may play a role, possibly in concert with other factors, in coordinating metamorphosis-associated changes in lipid metabolism.
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PMID:Effects of insulin on lipid metabolism of larvae and metamorphosing landlocked sea lamprey, Petromyzon marinus. 1033 28

Questions concerning whether malonyl-CoA is regulated in human muscle and whether malonyl-CoA modulates fatty acid oxidation are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentration of malonyl-CoA, citrate, and malate were determined in the vastus lateralis muscle of 16 healthy nonobese Swedish men during a sequential euglycemic-hyperinsulinemic clamp. Insulin was infused at rates of 0.25 and 1.0 mU x kg(-1) x min(-1), and glucose was infused at rates of 2.0 +/- 0.2 and 8.1 +/- 0.7 mg x kg(-1) x min(-1), respectively. During the low-dose insulin infusion, whole-body fatty acid oxidation, as determined by indirect calorimetry, decreased by 22% from a basal rate of 0.94 +/- 0.06 to 0.74 +/- 0.07 mg x kg(-1) x min(-1) (P = 0.005), but no increase in malonyl-CoA was observed. In contrast, during the high-dose insulin infusion, malonyl-CoA increased from 0.20 +/- 0.01 to 0.24 +/- 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional 41% to 0.44 +/- 0.06 mg x kg(-1) x min(-1) (P < 0.001). The increase in malonyl-CoA was associated with 30-50% increases in the concentrations of citrate (102 +/- 6 vs. 137 +/- 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme in the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 +/- 6 vs. 126 +/- 9 nmol/g, P = 0.002), an antiporter for citrate efflux from the mitochondria. Significant correlations were observed between the concentration of malonyl-CoA and both glucose utilization (r = 0.53, P = 0.002) and the sum of the concentrations of citrate and malate (r = 0.52, P < 0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA concentration and fatty acid oxidation was observed (r = -0.32, P = 0.03). The results indicate that an infusion of insulin and glucose at a high rate leads to increases in the concentration of malonyl-CoA in skeletal muscle and to decreases in whole-body and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that the increase in malonyl-CoA in this situation is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citrate is also an inhibitor of phosphofructokinase, an attractive hypothesis is that changes in its concentration are part of an autoregulatory mechanism by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle.
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PMID:Fatty acid oxidation and the regulation of malonyl-CoA in human muscle. 1090 61

Fatty acid oxidation in muscle has been reported to be diminished when insulin and glucose levels are elevated. This study was designed to determine whether activation of AMP-activated protein kinase (AMPK) will prevent inhibitory effects of insulin and glucose on the rate of fatty acid oxidation. Rat hindlimbs were perfused with medium containing 0, 0.3, or 60 nM insulin with or without 2 mM 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Glucose uptake was stimulated four- to fivefold by inclusion of insulin in the medium. Insulin attenuated the increase in AMPK caused by AICAR both in perfused hindlimbs and in isolated epitrochlearis muscles. The activation constant for citrate activation of acetyl-CoA carboxylase (ACC) was significantly increased in response to AICAR, and the increase was slightly attenuated if insulin was present in the perfusion medium. Insulin stimulated an increase in malonyl-CoA content of the muscles in the absence of AICAR. Malonyl-CoA was decreased to approximately the same value in AICAR-perfused muscle, regardless of insulin concentration. Muscle glucose 6-phosphate and citrate were significantly increased in response to AICAR and insulin. The rate of palmitate oxidation tended to decrease in response to insulin and in the absence of AICAR. AICAR increased palmitate oxidation to approximately the same level regardless of the insulin concentration or the rate of glucose uptake into the muscle. The rate of palmitate oxidation showed a curvilinear relationship as a function of muscle malonyl-CoA content, with half-maximal inhibition at approximately 0.6 nmol/g. We conclude that AMPK activation can prevent high rates of glucose uptake and glycolytic flux from inhibiting palmitate oxidation in predominantly fast-twitch muscle under these conditions.
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PMID:Insulin stimulation of glucose uptake fails to decrease palmitate oxidation in muscle if AMPK is activated. 1109 May 99

Acetyl-CoA carboxylase-alpha (ACC-alpha) plays a central role in co-ordinating de novo fatty acid synthesis in animal tissues. We have characterized the regulatory region of the ovine ACC-alpha gene. Three promoters, PI, PII and PIII, are dispersed throughout 50 kb of genomic DNA. Expression from PI is limited to adipose tissue and liver. Sequence comparison of the proximal promoters of ovine and mouse PIs demonstrates high nucleotide identity and that they are characterized by a TATA box at -29, C/EBP (CCAAT enhancer-binding protein)-binding motifs and multiple E-box motifs. A 4.3 kb ovine PI-luciferase reporter construct is insulin-responsive when transfected into differentiated ovine adipocytes, whereas when this construct is transfected into ovine preadipocytes and HepG2 cells the construct is inactive and is not inducible by insulin. By contrast, transfection of a construct corresponding to 132 bp of the proximal promoter linked to a luciferase reporter is active and inducible by insulin in all three cell systems. Insulin signalling to the -132 bp construct in differentiated ovine adipocytes involves, in part, an E-box motif at -114. Upstream stimulatory factor (USF)-1 and USF-2, but not sterol regulatory element-binding protein 1 (SREBP-1), are major components of protein complexes that bind this E-box motif. Activation of the 4.3 kb PI construct in differentiated ovine adipocytes is associated with endogenous expression of PI transcripts throughout differentiation; PI transcripts are not detectable by RNase-protection assay in ovine preadipocytes, HepG2 cells or 3T3-F442A adipocytes. These data indicate the presence of repressor motifs in PI that are required to be de-repressed during adipocyte differentiation to allow induction of the promoter by insulin.
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PMID:Promoter I of the ovine acetyl-CoA carboxylase-alpha gene: an E-box motif at -114 in the proximal promoter binds upstream stimulatory factor (USF)-1 and USF-2 and acts as an insulin-response sequence in differentiating adipocytes. 1158 73

Liver metabolism is influenced by hormones and nutrients. Amino acids such as glutamine or leucine induce an anabolic response, which resembles that of insulin in muscle and adipose tissue. In this work, the signalling pathways and the effects of insulin were compared to those of glutamine and leucine in isolated hepatocytes from normal and streptozotocin-diabetic rats. Glutamine increased cell volume and induced an anabolic response characterized by an activation of acetyl-CoA carboxylase (ACC), glycogen synthase (GS) and p70 ribosomal S6 kinase (p70S6K), the key enzymes in fatty acid, glycogen and protein synthesis, respectively. The effects of glutamine were independent of insulin and did not share its signalling components. Leucine, which is poorly metabolized by the liver and does not modify cell volume, activated ACC and p70S6K, and exerted a synergistic effect on the glutamine-induced activation of ACC and p70S6K. These amino acids did not affect insulin signalling. Insulin alone had no anabolic effect in hepatocytes, despite the activation of protein kinase B. Nevertheless, it enhanced the activation of ACC and p70S6K induced by leucine. However, insulin injected intravenously activated rat liver p70S6K. In hepatocytes from streptozotocin-diabetic animals, the metabolic responses to the amino acids and insulin were similar to those in normal hepatocytes. We conclude that glutamine, insulin and leucine exert different effects that are mediated by different signalling pathways, although their effects are combinatory. The anabolic effect of insulin in hepatocytes was strictly dependent on the permissive action of leucine.
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PMID:Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. 1215 71

AMP-activated protein kinase (AMPK) activation by AICAR (5-amino-imidazole carboxamide riboside) is correlated with increased glucose transport in rodent skeletal muscle via an insulin-independent pathway. We determined in vitro effects of insulin and/or AICAR exposure on glucose transport and cell-surface GLUT4 content in skeletal muscle from nondiabetic men and men with type 2 diabetes. AICAR increased glucose transport in a dose-dependent manner in healthy subjects. Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects. In contrast, insulin- and AICAR-stimulated responses on glucose transport and cell-surface GLUT4 content were impaired in subjects with type 2 diabetes. Importantly, exposure of type 2 diabetic skeletal muscle to a combination of insulin and AICAR increased glucose transport and cell-surface GLUT4 content to levels achieved in control subjects. AICAR increased AMPK and acetyl-CoA carboxylase phosphorylation to a similar extent in skeletal muscle from subjects with type 2 diabetes and nondiabetic subjects. Our studies highlight the potential importance of AMPK-dependent pathways in the regulation of GLUT4 and glucose transport activity in insulin-resistant skeletal muscle. Activation of AMPK is an attractive strategy to enhance glucose transport through increased cell surface GLUT4 content in insulin-resistant skeletal muscle.
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PMID:5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. 1271 34


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