Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although it has been documented that hormones promote lipolysis in the heart, an enzyme mediating this event has not been identified. We have found that perfusion of the rat heart with epinephrine, 3-isobutyl-1-methylxanthine, or dibutyryl (Bt2) cyclic AMP produced a biphasic effect on the activity of an enzyme having the properties of the intracellular fraction of lipoprotein lipase, i.e., stability in acetone:ether, pH optimum of 8.1, serum requirement, and sensitivity to heparin, NaCl, and protamine sulfate. We have termed this enzyme type L hormone-sensitive lipase (HSL). Perfusion with high concentrations of agent stimulate type L HSL activity, while perfusion with relatively low concentrations of agent inhibit enzyme activity. This inhibition is not observed if enzyme is extracted in organic solvent. The activity of type L HSL has a high negative (r greater than -0.93) relationship with the amount of triglyceride in the heart. Early attempts to purify this enzyme from control and epinephrine-stimulated hearts suggest that the enzyme can be obtained in two forms (control and activated). Although the data suggest that the mechanism of control of this enzyme is complex, it seems that the activity is controlled, in part, through cyclic AMP and protein kinase.
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PMID:Hormonal regulation of myocardial lipolysis. 631 45

Endogenous lipid droplets were prepared by subjecting fat cells to hypotonic shock and to Triton X-100 treatment. The structure of the endogenous lipid droplet fraction was examined by scanning and transmission electron microscopies. Neither intact fat cells nor disrupted cell membranes were detectable in the endogenous lipid droplet fraction. With this endogenous substrate, epinephrine elicited lipolysis with either hormone-sensitive lipase or lipoprotein lipase, but no cyclic AMP-protein kinase mediated stimulation of lipolysis was observed. On the other hand, epinephrine did not stimulate lipolysis when triolein emulsified with arabic gum was used as substrate. With the latter exogenous substrate, however, cyclic AMP-protein kinase was found to stimulate lipolysis with hormone-sensitive lipase as enzyme. These results agree with the proposal of Wise and Jungas that the epinephrine-stimulated increase of hydrolysis of endogenous fat is not mediated through cyclic AMP-protein kinase. A possible mechanism of hydrolysis of endogenous fat by induction of lipolysis by epinephrine in fat cells is discussed.
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PMID:Role of endogenous lipid droplets of fat cells in epinephrine-induced lipolysis. 684 55

In this review, we evaluate the relative regulatory importance of specific strategic enzymes (in particular glycogen synthase, acetyl-CoA carboxylase [ACC] and the pyruvate dehydrogenase complex [PDH]) for carbohydrate utilization as an anabolic precursor and as an energy substrate during the nutritional transitions between the fed and fasted states. The involvement of the specific protein kinases contributing to the inactivation of these enzymes by phosphorylation [cyclic AMP-dependent protein kinase, AMP-activated protein kinase and PDH kinase] in achieving each regulatory response is also assessed. We demonstrate a striking temporal correlation between hepatic glycogen mobilization and PDH and ACC inactivation by phosphorylation during the immediate postabsorptive period; in contrast, rates of hepatic glycogen synthesis and PDH and ACC expressed activities do not change in parallel during refeeding. The results are consistent with shifting of the primary sites of control for overall hepatic carbon flux during the fed-to-starved and starved-to-fed nutritional transitions achieved, at least in part, by a complex pattern of regulation by protein phosphorylation and metabolites which is critically dependent on the precise nutritional status. Data are also presented that demonstrate asynchronous suppression of glucose uptake/phosphorylation and pyruvate oxidation in cardiac and skeletal muscle during progressive starvation. Analogous asynchrony is observed in the reactivation of these processes in cardiac and skeletal muscle during refeeding after starvation. We provide evidence in support of the concept that selective suppression of pyruvate oxidation in oxidative muscles during early starvation and during the initial phase of refeeding is achieved because of differential sensitivity of glucose uptake/phosphorylation and pyruvate oxidation to lipid-fuel utilization. We discuss the relative importance of regulatory events governing local fatty acid production and utilization (via lipoprotein lipase and carnitine palmitoyltransferase 1, respectively) or overall fatty acid supply (dictated by events at the adipocyte) for fuel utilization by muscle during nutritional transitions. Finally, we assess the regulatory importance of glycogen synthesis in determining overall rates of glucose clearance by skeletal muscle during alimentary hyperglycemia and hyperinsulinemia.
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PMID:Mechanisms involved in the coordinate regulation of strategic enzymes of glucose metabolism. 810 32

GH has been previously shown in Ob1771 adipose cells to activate transiently the expression of c-fos gene by a protein kinase-C-dependent pathway and to modulate, at last in part by a protein kinase-C-dependent pathway, the expression of the lipoprotein lipase (LPL) gene. In Ob1771 cells exposed to GH, under conditions where protein synthesis is inhibited by cycloheximide, the modulation of LPL gene expression is prevented, suggesting that synthesis of trans-acting factor(s) is required to modulate LPL gene expression. The present results indicate the involvement of c-Fos protein in this modulation; this involvement is supported by various lines of evidence: 1) upon GH stimulation, the increase in c-fos mRNA content is followed by the emergence of c-Fos protein within the nucleus, and this emergence precedes the increase in LPL mRNA content; 2) in GH-treated Ob1771 cells, exposure to antisense sof oligonucleotides abolishes the synthesis of c-Fos protein; and 3) at the same time, the increase in LPL mRNA content and LPL activity does not occur, whereas sense fos oligonucleotides show no effect. It is concluded that c-Fos protein plays an intermediary role in the modulation of LPL gene expression by GH.
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PMID:The regulation by growth hormone of lipoprotein lipase gene expression is mediated by c-fos protooncogene. 841 45

Mechanisms of the stimulatory release of lipoprotein lipase (LPL) activity from isolated rat fat pads by sodium orthovanadate (vanadate) were studied through a cAMP-dependent process. A potent inhibitor of insulin receptor tyrosine kinase, quercetin, inhibited the vanadate-increasing effect on the LPL activity in fat pads, but did not inhibit the vanadate-stimulated release of LPL activity from the fat pads. Propranolol and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8) decreased the vanadate-stimulated release in a dose-dependent manner. Isoproterenol and dibutyryl cAMP (Bt2cAMP) stimulated the release of LPL activity from fat pads. Vanadate, as well as isoproterenol, rapidly increased the cAMP content in fat pads, and this increase was almost completely inhibited by propranolol. Vanadate increased the cAMP-dependent protein kinase (PKA) activity ratios calculated from the measurement in the presence or absence of cAMP or PKa inhibitor. These results suggest that the vanadate-stimulated release of LPL activity is associated with a process involving a rapid increase in the cAMP content accompanied by the activation of PKA.
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PMID:Involvement of the rapid increase in cAMP content in the vanadate-stimulated release of lipoprotein lipase activity from rat fat pads. 895 Nov 55

Astilbin, a dihydroflavonol rhamnoside isolated from the leaves of Engelhardtia chrysolepis, enhanced the vanadate-stimulated release of lipoprotein lipase (LPL) activity from rat isolated fat pads. N-[2-(Methyl-amino)ethyl]-5-isoquinolinesulfonamide (H-8), a potent inhibitor of cAMP-dependent protein kinase (PKA), markedly inhibited the enhancement by astilbin. Lipolysis in the fat pads was stimulated by astilbin alone in a dose-dependent manner and this stimulation was suppressed in the presence of vanadate, probably due to its antilipolytic action. A significant enhancement by astilbin was observed with increasing effects of vanadate on cAMP content in the fat pads and on cAMP phosphodiesterase (PDE) activity in the particulate fraction although astilbin alone showed only a slight increase in the cellular cAMP content and PDE activity. Astilbin may enhance the vanadate-stimulated release of LPL activity through a synergistic effect on an increase in the cellular cAMP content produced by vanadate accompanied by more potent activation of PKA.
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PMID:Enhancement of the vanadate-stimulated release of lipoprotein lipase activity by astilbin from the leaves of Engelhardtia chrysolepis. 963 10

The excess of glucose appears to play an important and specific role in the genesis of macroangiopathy in diabetics. Activation of protein kinase-C, the sorbitol pathway, and AGE formation are thought to be the major pathways linking the degree of glycaemic compensation with the pathogenetic process of macrovascular disease. HSPG is likely to be a key element in this process since it is a regulator of endothelial permeability, vascular antithrombotic capacity, insulin sensitivity (with respect to lipoprotein lipase availability), and vascular extracellular matrix content and smooth-muscle-cell activation. Loss of HSPG is suggested clinically by the presence of microalbuminuria, to the development of which diabetic control also contributes significantly. However, genetic factors also seem to be involved. Much more insight into the precise mechanismus is necessary to unravel the cellular and molecular chains of events for the premature and accelerated atherosclerosis in diabetic patients.
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PMID:The atherosclerotic process and its exacerbation by diabetes. 1146 May 93

The balance of lipid flux in adipocytes is controlled by the opposing actions of lipolysis and lipogenesis, which are controlled primarily by hormone-sensitive lipase and lipoprotein lipase (LPL), respectively. Catecholamines stimulate adipocyte lipolysis through reversible phosphorylation of hormone-sensitive lipase, and simultaneously inhibit LPL activity. However, LPL regulation is complex and previous studies have described translational regulation of LPL in response to catecholamines because of an RNA-binding protein that interacts with the 3'-untranslated region of LPL mRNA. In this study, we identified several protein components of an LPL RNA binding complex. Using an LPL RNA affinity column, we identified two of the RNA-binding proteins as the catalytic (C) subunit of cAMP-dependent protein kinase (PKA), and A kinase anchoring protein (AKAP) 121/149, one of the PKA anchoring proteins, which has known RNA binding activity. To determine whether the C subunit was involved in LPL translation inhibition, the C subunit was depleted from the cytoplasmic extract of epinephrine-stimulated adipocytes by immunoprecipitation. This resulted in the loss of LPL translation inhibition activity of the extract, along with decreased RNA binding activity in a gel shift assay. To demonstrate the importance of the AKAPs, inhibition of PKA-AKAP binding with a peptide competitor (HT31) prevented epinephrine-mediated inhibition of LPL translation. C subunit kinase activity was necessary for LPL RNA binding and translation inhibition, suggesting that the phosphorylation of AKAP121/149 or other proteins was an important part of RNA binding complex formation. The hormonal activation of PKA results in the reversible phosphorylation of hormone-sensitive lipase, which is the primary mediator of adipocyte lipolysis. These studies demonstrate a dual role for PKA to simultaneously inhibit LPL-mediated lipogenesis through inhibition of LPL translation.
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PMID:The translational regulation of lipoprotein lipase by epinephrine involves an RNA binding complex including the catalytic subunit of protein kinase A. 1221 46

The effects of vanadate on lipoprotein lipase (LPL), a lipid-metabolizing enzyme, were tested using isolated rat fat pads. Vanadate increased the cellular LPL content through the stimulation of intracellular transport of the enzyme for activation, probably glycosylation. The stimulated release of LPL from the fat pads by vanadate was due to the increase in intracellular Ca2+ concentration, leading to the fusion of plasma membrane with vehicle included active LPL. Although vanadate shows insulin- and heparin-mimicking effects, it appears to differ from both insulin and heparin with regard to the mechanism of action. In isolated mouse fat pads, vanadate decreased the cellular leptin content and secretion by the increased degradation via a cAMP/PKA-dependent process involving proteasome activation and/or ubiquitination. This was the reverse of the action of insulin. In hepatocytes, cAMP phosphodiesterase type 3 activity was stimulated via the increased mitogen-activated protein kinase activity by vanadate. On the other hand, the stimulation by insulin was dependent on Akt kinase activation. The effects of vanadate were additive to those of insulin, suggesting that vanadate differs from insulin with regard to the receptor-signaling cascade. Furthermore, vanadate showed antiplatelet and antithrombin activity, leading to the prolongation of blood clotting time.
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PMID:[New biological actions of vanasium]. 1293 59

Hormone-sensitive lipase (HSL) is a rate-limiting enzyme in lipolysis that displays broad substrate specificity. HSL function is regulated by reversible phosphorylation that occurs within a 150 aa "regulatory module" of the protein. The current studies used mutational analysis to dissect the contribution of the "regulatory module" in HSL activity and substrate specificity. Deletion of the entire "regulatory module" or replacement of the "regulatory module" with the "lid" of lipoprotein lipase resulted in enzymatically inactive proteins. Deletion of sequentially longer stretches of the "regulatory module" resulted in a stepwise reduction in hydrolytic activity. Analysis of 7-19 amino acid deletional mutants that spanned the "regulatory module" showed that the N-terminal partial deletion mutants retained normal hydrolytic activity and activation by PKA. In contrast, the C-terminal partial deletion mutants displayed reduced hydrolytic activities, with preferential loss of activity against lipid-, as opposed to water-soluble, substrates. Single amino acid mutations of F650C, P651A, and F654D reduced activity against lipid-, but not water-soluble, substrates. The current results suggest that the length of the "regulatory module" and specific sequences within the C-terminal portion of the "regulatory module" of HSL (amino acids 644-683) are crucial for activity and appear to be responsible for determining lipase activity.
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PMID:Mutational analysis of the "regulatory module" of hormone-sensitive lipase. 1569 20


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