Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the mechanisms responsible for the anti-lipolytic effect of intracellular Ca2+ ([Ca2+]i) in human adipocytes. Increasing [Ca2+]i inhibited lipolysis induced by b-adrenergic receptor activation, A1 adenosine receptor inhibition, adenylate cyclase activation, and phosphodiesterase (PDE) inhibition, as well as by a hydrolyzable cAMP analog, but not by a nonhydrolyzable cAMP analog. This finding indicates that the anti-lipolytic effect of [Ca2+]i may be mediated by the activation of adipocyte PDE. Consistent with this theory, [Ca2+]i inhibition of isoproterenol-stimulated lipolysis was reversed completely by the nonselective PDE inhibitor isobutyl methylxanthine and also by the selective PDE 3B inhibitor cilostamide, but not by selective PDE 1 and 4 inhibitors. In addition, phosphatidylinositol-3 kinase inhibition with wortmannin completely prevented insulin's anti-lipolytic effect but only minimally blocked [Ca2+]i's effect, which suggests that [Ca2+]i and insulin may activate PDE 3B via different mechanisms. In contrast, the antilipolytic effect of [Ca2+]i was not affected by inhibitors of calmodulin, Ca2+/calmodulin-dependent kinase, protein phosphatase 2B, and protein kinase C. Finally, [Ca2+]i inhibited significantly isoproterenol-stimulated increases in cAMP levels and hormone-sensitive lipase phosphorylation in human adipocytes. In conclusion, increasing [Ca2+]i exerts an antilipolytic effect mainly by activation of PDE, leading to a decrease in cAMP and HSL phosphorylation and, consequently, inhibition of lipolysis.
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PMID:Mechanism of intracellular calcium ([Ca2+]i) inhibition of lipolysis in human adipocytes. 1164 Dec 62

Intramuscular triacylglycerol is an important energy store and is also related to insulin resistance. The mobilization of fatty acids from this pool is probably regulated by hormone-sensitive lipase (HSL), which has recently been shown to exist in muscle and to be activated by both adrenaline and contractions. Adrenaline acts via cAMP-dependent protein kinase (PKA). The signalling mediating the effect of contractions is unknown and was explored in this study. Incubated soleus muscles from 70 g male rats were electrically stimulated to perform repeated tetanic contractions for 5 min. The contraction-induced activation of HSL was abolished by the protein kinase C (PKC) inhibitors bisindolylmaleimide I and calphostin C and reduced 50% by the mitogen-activated protein kinase kinase (MEK) inhibitor U0126, which also completely blocked extracellular signal-regulated kinase (ERK) 1 and 2 phosphorylation. None of the inhibitors reduced adrenaline-induced HSL activation in soleus muscle. Both phorbol-12-myristate-13-acetate (PMA), which activates PKC and, in turn, ERK, and caffeine, which increases intracellular Ca2+ without eliciting contraction, increased HSL activity. Activated ERK increased HSL activity in supernatant from basal but not from electrically stimulated muscle. In conclusion, in muscle, PKC can stimulate HSL through ERK. Contractions and adrenaline enhance muscle HSL activity by different signalling mechanisms. The effect of contractions is mediated by PKC, at least partly via the ERK pathway.
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PMID:Contractions activate hormone-sensitive lipase in rat muscle by protein kinase C and mitogen-activated protein kinase. 1279 77

Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acyl-CoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial beta-oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states.
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PMID:Fatty acid metabolism and insulin secretion in pancreatic beta cells. 1368 Jan 27

Intramyocellular triglyceride is an important energy store which is related to insulin resistance. Mobilization of fatty acids from this pool is probably regulated by hormone-sensitive lipase (HSL), which has recently been shown to exist in muscle and to be activated by epinephrine via PKA and by contractions via PKC and ERK. 5' AMP-activated protein kinase (AMPK) is an intracellular fuel gauge which regulates metabolism. In this study we incubated rat soleus muscle to investigate if AMPK influences HSL during 5min of repeated tetanic contractions. An eightfold increase in AMPK activity was accompanied by a 2.5-fold increase in phosphorylation of the AMPK-site Ser(565) in HSL (p<0.05). Inhibition of PKC by Calphostin C abolished the contraction-mediated HSL activation while HSL-Ser(565) phosphorylation was not reduced. The study indicates that during contractions AMPK phosphorylates HSL in Ser(565), but this phosphorylation is not directly responsible for the contraction-induced activation of HSL.
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PMID:Contractions induce phosphorylation of the AMPK site Ser565 in hormone-sensitive lipase in muscle. 1503 81

In the present study, we investigate the coherence of signaling pathways leading to lipolysis in 3T3-L1 adipocytes. We observe two linear signaling pathways: one well known, acting via cAMP and protein kinase A (PKA) activation, and a second one induced by phorbol 12-myristate 13-acetate treatment involving protein kinase C (PKC) and MAPK. We demonstrate that both the PKA regulatory subunits RIalpha and RIIbeta are expressed in 3T3-L1 adipocytes and are responsible for the lipolytic effect mediated via the cAMP/PKA pathway. Inhibition of the PKA pathway by the selective PKA inhibitor Rp-8-CPT-cAMPS does not impair lipolysis induced by PKC activation, and neither PD98059 nor U0126, as known MAPK kinase inhibitors, changes the level of glycerol release caused by PKA activation, indicating no cross-talk between these two pathways when only one is activated. However, when both are activated, they act synergistically on glycerol release. Additional experiments focusing on this synergy show no involvement of MAPK phosphorylation and cAMP formation. Phosphorylation of hormone-sensitive lipase is similar upon stimulation of either pathway, but we demonstrate a difference in the ability of both PKA and the PKC pathway activation to phosphorylate perilipin, which in turn may be an explanation for the different maximal lipolytic effect of both pathways.
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PMID:Cooperative activation of lipolysis by protein kinase A and protein kinase C pathways in 3T3-L1 adipocytes. 1528 93

Intramyocellular triacylglycerol (TG) is an important energy store, and the energy content of this depot is higher than the energy content of the muscle glycogen depot. It has recently been shown that the mobilization of fatty acids from this TG pool may be regulated by the neutral lipase hormone-sensitive lipase (HSL). This enzyme is known to be rate limiting for intracellular TG hydrolysis in adipose tissue. The presence of HSL has been demonstrated in all muscle fibre types by Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying. The content of HSL varies between fibre types, being higher in oxidative fibres than in glycolytic fibres. When analysed under conditions optimal for HSL, neutral lipase activity in muscle can be stimulated by adrenaline as well as by contractions. These increases are abolished by the presence of anti-HSL antibody during analysis. Moreover, immunoprecipitation with affinity-purified anti-HSL antibody causes similar reductions in muscle HSL protein concentration and in measured neutral lipase responses to contractions. The immunoreactive HSL in muscle is stimulated by adrenaline via beta-adrenergic activation of cAMP-dependent protein kinase (PKA). From findings in adipocytes it is likely that PKA phosphorylates HSL at residues Ser(563), Ser(659) and Ser(660). Contraction probably also enhances muscle HSL activity by phosphorylation, because the contraction-induced increase in HSL activity is elevated by the protein phosphatase inhibitor okadaic acid and reversed by alkaline phosphatase. A novel signalling pathway in muscle by which HSL activity may be stimulated by protein kinase C (PKC) via extracellular signal-regulated kinase (ERK) has been demonstrated. In contrast to previous findings in adipocytes, in muscle the activation of ERK is not necessary for stimulation of HSL by adrenaline. However, contraction-induced HSL activation is mediated by PKC, at least partly via the ERK pathway. In fat cells ERK is known to phosphorylate HSL at Ser(600). Hence, phosphorylation of different sites may explain the finding that in muscle the effects of contractions and adrenaline on HSL activity are partially additive. In line with the view that the two stimuli act by different mechanisms, training increases contraction-mediated HSL activation but diminishes adrenaline-mediated HSL activation in muscle. In conclusion, HSL is present in skeletal muscle and can be activated by phosphorylation in response to both adrenaline and muscle contractions. Training increases contraction-mediated HSL activation, but decreases adrenaline-mediated HSL activation in muscle.
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PMID:Regulation and role of hormone-sensitive lipase in rat skeletal muscle. 1529 48

To explore the functional effects of hormone-sensitive lipase (HSL) in diacylglycerol (DAG) metabolism, Chinese hamster ovary cells were stably transfected with rat HSL cDNA (wt-HSL), inactive mutant S423A-HSL cDNA (S423A) and pcDNA3 vector alone (Ct). [(14)C]Glucose-incorporation into triglyceride (TG) was 75% lower in the presence or absence of insulin in cells expressing wt-HSL compared to Ct or S423A. [(14)C]Glucose-incorporation into DAG was 33% lower without insulin and 51% lower with insulin in cells expressing wt-HSL compared to Ct or S423A. Insulin stimulated glucose-incorporation into DAG 2.2-fold in S423A and Ct cells, whereas only a 50% increase was observed in cells expressing wt-HSL. Phospholipase C-mediated release of DAG from membrane phospholipids was reduced 70% in cells expressing wt-HSL compared to Ct or S423A. Western blot analysis showed that membrane-bound protein kinase C (PKC)-alpha and -epsilon were decreased 40-50% in cells expressing wt-HSL grown in high glucose with insulin. These data show that HSL potentially hydrolyzes cellular DAG generated either by de novo synthesis from glucose or release from membrane phospholipids by phospholipase C, resulting in a reduction in the translocation of DAG-sensitive PKCs.
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PMID:Function of hormone-sensitive lipase in diacylglycerol-protein kinase C pathway. 1533 Dec

Sex steroid hormones are involved in the metabolism, accumulation and distribution of adipose tissues. It is now known that oestrogen receptor, progesterone receptor and androgen receptor exist in adipose tissues, so their actions could be direct. Sex steroid hormones carry out their function in adipose tissues by both genomic and nongenomic mechanisms. In the genomic mechanism, the sex steroid hormone binds to its receptor and the steroid-receptor complex regulates the transcription of given genes. Leptin and lipoprotein lipase are two key proteins in adipose tissues that are regulated by transcriptional control with sex steroid hormones. In the nongenomic mechanism, the sex steroid hormone binds to its receptor in the plasma membrane, and second messengers are formed. This involves both the cAMP cascade and the phosphoinositide cascade. Activation of the cAMP cascade by sex steroid hormones would activate hormone-sensitive lipase leading to lipolysis in adipose tissues. In the phosphoinositide cascade, diacylglycerol and inositol 1,4,5-trisphosphate are formed as second messengers ultimately causing the activation of protein kinase C. Their activation appears to be involved in the control of preadipocyte proliferation and differentiation. In the presence of sex steroid hormones, a normal distribution of body fat exists, but with a decrease in sex steroid hormones, as occurs with ageing or gonadectomy, there is a tendency to increase central obesity, a major risk for cardiovascular disease, type 2 diabetes and certain cancers. Because sex steroid hormones regulate the amount and distribution of adipose tissues, they or adipose tissue-specific selective receptor modulators might be used to ameliorate obesity. In fact, hormone replacement therapy in postmenopausal women and testosterone replacement therapy in older men appear to reduce the degree of central obesity. However, these therapies have numerous side effects limiting their use, and selective receptor modulators of sex steroid hormones are needed that are more specific for adipose tissues with fewer side effects.
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PMID:Direct effects of sex steroid hormones on adipose tissues and obesity. 1545 95

Acyl homoserine lactones are synthesized by Pseudomonas aeruginosa as signaling molecules which control production of virulence factors and biofilm formation in a paracrine manner. We found that N-(3-oxododecanoyl)-L-homoserine lactone (3OC12-HSL), but not its 3-deoxo isomer or acyl-homoserine lactones with shorter fatty acids, induced the directed migration (chemotaxis) of human polymorphonuclear neutrophils (PMN) in vitro. By use of selective inhibitors a signaling pathway, comprising phosphotyrosine kinases, phospholipase C, protein kinase C, and mitogen-activated protein kinase C, could be delineated. In contrast to the well-studied chemokines complement C5a and interleukin 8, the chemotaxis did not depend on pertussis toxin-sensitive G proteins, indicating that 3OC12-HSL uses another signaling pathway. Strong evidence for the presence of a receptor for 3OC12-HSL on PMN was derived from uptake studies; by use of radiolabeled 3OC12-HSL, specific and saturable binding to PMN was seen. Taken together, our data provide evidence that PMN recognize and migrate toward a source of 3OC12-HSL (that is, to the site of a developing biofilm). We propose that this early attraction of PMN could contribute to prevention of biofilm formation.
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PMID:Induction of neutrophil chemotaxis by the quorum-sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone. 1698 44

Bacterial endotoxin/lipopolysaccharide elicits inflammatory responses and also elevates circulating levels of free fatty acids (FFAs) and impairs insulin sensitivity. Serum FFA elevation in acute endotoxemia has long been thought to be due to endotoxin dysregulating lipid disposal and counterregulatory hormones and cytokines. Here, we investigated the direct lipolysis effect of endotoxin in rodents and in isolated primary adipocytes. Endotoxin increases lipolysis in vivo in adipose tissues, elevates circulating FFA level, induces insulin resistance in rats, and directly stimulates chronic lipolysis in vitro in adipocytes. The lipolytic action of endotoxin is mediated via its lipid A moiety and is blocked by anti-endotoxin peptides. Neither adipocytokine secretion nor nuclear factor-kappaB activation is involved in endotoxin-induced lipolysis. Different from catecholamine, endotoxin stimulates lipolysis without elevating cAMP production and activating protein kinase A and protein kinase C. Instead, endotoxin induces phosphorylation of Raf-1, MEK1/2, and ERK1/2. Upon inhibition of ERK1/2 but not JNK and p38 MAPK, endotoxin-stimulated lipolysis ceases. Endotoxin causes perilipin down-regulation and phosphorylation and increases the activity and protein levels of hormone-sensitive lipase and adipose triglyceride lipase but does not induce hormone-sensitive lipase translocation to intracellular lipid droplets. In TLR4 (Toll-like receptor 4)-deficient mice and adipocytes, endotoxin fails to increase in vivo and in vitro lipolysis. These findings suggest that endotoxin stimulates lipolysis via TLR4 and ERK1/2 signaling in adipocytes. The lipolytic action of endotoxin liberates FFA efflux from adipocytes to the bloodstream, which is a possible basis for systemic FFA elevation and insulin resistance in endotoxemia or Gram-negative bacterial infection.
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PMID:Bacterial endotoxin stimulates adipose lipolysis via toll-like receptor 4 and extracellular signal-regulated kinase pathway. 1912 98


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