Enhancing T3 and cAMP responsive gene participation in the thermogenic regulation of fuel oxidation pathways

Dorsa, Karina Kores; Santos, Michelle Venâncio dos; Silva, Magnus R. Dias da

doi:10.1590/s0004-27302010000400007

Cited by 10 publications

(9 citation statements)

References 41 publications

(43 reference statements)

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“…Hence, engaging negative cAMP‐PKA signaling is essential for maintaining liver homeostasis in the presence of an IR insult. Many cellular effects of cAMP, including cell differentiation, proliferation, and apoptosis, can be mediated by PKA 5, 6. Triggering cAMP‐PKA activation has been shown to regulate immune responses7‐9 and promote parenchymal cell survival 10‐12.…”

Section: Discussionmentioning

confidence: 99%

“…Many cellular effects of cAMP, including cell differentiation, proliferation, and apoptosis, can be mediated by PKA. 5,6 Triggering cAMP-PKA activation has been shown to regulate immune responses 7-9 and promote parenchymal cell survival. [10][11][12] In addition, a recent study has revealed that the activation of cAMP-PKA blocks the mitochondrial permeability transition and protects cultured rat hepatocytes from anoxiainduced cell death in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Protein kinase A (PKA) binds cAMP via a complex of catalytic and mutant regulatory subunits 5. The activation of cAMP‐dependent PKA leads to an array of regulatory cell functions, including proliferation, differentiation, apoptosis, migration, and immune responses 5‐7. Recent studies have documented that the activation of cAMP‐PKA signaling inhibited the TLR4 response, by increasing IL‐10 and suppressing macrophage levels of proinflammatory TNF‐α and macrophage inflammatory protein 1α in vitro 8.…”

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confidence: 99%

“…5 The activation of cAMP-dependent PKA leads to an array of regulatory cell functions, including proliferation, differentiation, apoptosis, migration, and immune responses. [5][6][7] Recent studies have documented that the activation of cAMP-PKA signaling inhibited the TLR4 response, by increasing IL-10 and suppressing macrophage levels of proinflammatory TNF-a and macrophage inflammatory protein 1a in vitro. 8 The mechanism by which the cAMP-PKA axis suppresses LPS-induced TNF-a production involves increases in the activity of cyclic adenosine monophosphate response element-binding protein (CREB) and the modulation of nuclear factor kappa B (NF-jB).…”

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confidence: 99%

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Activation of cyclic adenosine monophosphate-dependent protein kinase a signaling prevents liver ischemia/reperfusion injury in mice

Shen

Gao

et al. 2012

Liver Transpl

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Hepatic ischemia and reperfusion injury (IRI) occurs in multiple clinical settings including liver transplantation. Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway inhibits hepatocellular apoptosis and regulates TLR4-triggered inflammation responses in vitro. Here, we examined the function and therapeutic potential of cAMP-PKA activation in a murine (C57/BL6) model of liver warm ischemia (90 min) followed by reperfusion. Liver IRI triggered cAMP-PKA activation, whereas administration of its specific inhibitor, H-89, exacerbated hepatocellular damage. Conversely, Forskolin therapy, which activates PKA by elevating cAMP levels, protected livers from IRI, evidenced by diminished serum ALT and well-preserved tissue architecture. Liver protection rendered by cAMP-PKA stimulation was accompanied by diminished neutrophil and macrophage infiltration/activation, reduced hepatocyte necrosis/apoptosis, yet increased cAMP response element-binding protein (CREB) and augmented IL-10 expression. Neutralization of IL-10 restored liver damage in otherwise IR-resistant Forskolin-treated mice. In vitro, cAMP-PKA activation diminished macrophage TNF-α/IL-6/IL-12 in an IL-10-dependent manner, and prevented necrosis/apoptosis in primary mouse hepatocyte cultures. Our novel findings in a mouse model of liver IRI document the importance of cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Activation of cAMP-PKA signaling differentially regulates local inflammation and prevents hepatocyte death, providing the rationale for novel therapeutic approaches to combat liver IRI in transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Activation of cyclic adenosine monophosphate-dependent protein kinase a signaling prevents liver ischemia/reperfusion injury in mice

Shen

Gao

et al. 2012

Liver Transpl

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“…In the combined group, T3 impeded the increases of tumor proteins SYP and VEGF; and in vitro, T3 prevented VEGF secretion, neurite-like outgrowth and invasive capacity. It is well established that T3 acts synergistically with β-adrenergic pathways to upregulate genes that contain both CRE and TRE sites (68,69), but there is also evidence that T3 represses the expression of genes that have only CRE sites (29,70,71). The lack of TRE sites on genes associated with NE differentiation and cell invasion can explain the null effect of T3 on the basal expression of these genes, suggesting that T3 acts indirectly in the ISO response.…”

Section: Discussionmentioning

confidence: 99%

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Delgado‐González

Sánchez-Tusié

Morales

et al. 2016

Mol Med

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Prostate cancer cells are responsive to adrenergic and thyroid stimuli. It is well established that β-adrenergic activation (protein kinase A [PKA]/cAMP response element binding protein [CREB]) promotes cancer progression, but the role of thyroid hormones is poorly understood. We analyzed the effects of β-adrenergic stimulation (isoproterenol [ISO]) and/or thyroid hormone on neuroendocrine (NE) differentiation and cell invasion, using in vivo (LNCaP tumor) and in vitro models (LNCaP and DU145 human cells). Nude mice were inoculated with LNCaP cells and were treated for 6 wks with ISO (200 μg/d), triiodothyronine (T3, 2.5 μg/d) or both. ISO alone reduced tumor growth but increased tumor expression of cAMP response element (CRE)-dependent genes (real-time polymerase chain reaction, chromogranin A, neuron-specific enolase, survivin, vascular endothelial growth factor [VEGF], urokinase plasmin activator [uPA] and metalloproteinase-9 [MMP-9]) and some proteins related to NE differentiation and/or invasiveness (synaptophysin, VEGF, pCREB). T3 reduced tumor growth and prevented the overexpression of ISO-stimulated factors through a pCREB-independent mechanism. In low invasive LNCaP cells, 50 μmol/L ISO or 100 nmol/L thyroxine (T4) induced the acquisition of NE-like morphology (phase-contrast microscopy), increased VEGF secretion (ELISA) and invasive capacity (Transwell assay), but no synergistic effects were observed after the coadministration of ISO + T4. In contrast, 10 nmol/L T3 alone had no effect, but it prevented the NE-like morphology and invasiveness stimulated by ISO. None of these treatments had any effect on highly invasive DU145 cells. In summary, this study showed that ISO and T4 increase cancer progression, and T3 attenuates ISO-stimulated progression. Further studies are required to determine if changes in the ratio of T4/T3 could be relevant for prostate cancer progression.

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Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction

Ramsden

et al. 2012

Brain and Behavior

107

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Uncoupling proteins (UCPs) belong to a large family of mitochondrial solute carriers 25 (SLC25s) localized at the inner mitochondrial membrane. UCPs transport protons directly from the intermembrane space to the matrix. Of five structural homologues (UCP1 to 5), UCP4 and 5 are principally expressed in the central nervous system (CNS). Neurons derived their energy in the form of ATP that is generated through oxidative phosphorylation carried out by five multiprotein complexes (Complexes I–V) embedded in the inner mitochondrial membrane. In oxidative phosphorylation, the flow of electrons generated by the oxidation of substrates through the electron transport chain to molecular oxygen at Complex IV leads to the transport of protons from the matrix to the intermembrane space by Complex I, III, and IV. This movement of protons to the intermembrane space generates a proton gradient (mitochondrial membrane potential; MMP) across the inner membrane. Complex V (ATP synthase) uses this MMP to drive the conversion of ADP to ATP. Some electrons escape to oxygen-forming harmful reactive oxygen species (ROS). Proton leakage back to the matrix which bypasses Complex V resulting in a major reduction in ROS formation while having a minimal effect on MMP and hence, ATP synthesis; a process termed “mild uncoupling.” UCPs act to promote this proton leakage as means to prevent excessive build up of MMP and ROS formation. In this review, we discuss the structure and function of mitochondrial UCPs 4 and 5 and factors influencing their expression. Hypotheses concerning the evolution of the two proteins are examined. The protective mechanisms of the two proteins against neurotoxins and their possible role in regulating intracellular calcium movement, particularly with regard to the pathogenesis of Parkinson's disease are discussed.

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Enhancing T3 and cAMP responsive gene participation in the thermogenic regulation of fuel oxidation pathways

Abstract: Our results point to other enzymes which may possibly be regulated by T3 and CREB, and speculate their joint roles in contributing to the optimal thermogenic acclimation.

Cited by 10 publications

References 41 publications

Activation of cyclic adenosine monophosphate-dependent protein kinase a signaling prevents liver ischemia/reperfusion injury in mice

Activation of cyclic adenosine monophosphate-dependent protein kinase a signaling prevents liver ischemia/reperfusion injury in mice

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction

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