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183 results on '"Stroka D"'

1. Intracellular Proprotein convertase subtilisin/kexin type 9: Recruitment and regulatory role in mitochondrial architecture and bioenergetic

Author

Gavini, J, Leuenberger, D, Yarahmadov, T, Dommann, N, Keogh, A, Melin, N, Tschan, M, Nuoffer, J-M, Hertig, D, Zuber, B, Odriozola, A, Tombolini, R, Chrétien, M, Mbikay, M, Candinas, D, and Stroka, D

Subjects
570 Life sciences, biology, Surgery, 610 Medicine & health
Abstract

Objective Circulating Proprotein convertase subtilisin/kexin type 9 (PCSK9) captured the scientific community's attention as powerful target to fight against high serum cholesterol and its associated adverse consequences. Despite the well-described role of PCSK9 in impairing the recycling of low-density lipoprotein receptor (LDLR) on hepatocytes, its intracellular importance in metabolism modulations remain largely unexplored. Here, we describe a novel intracellular function of PCSK9 in hepatocyte metabolism and in liver regeneration. Methods A surgical model of partial hepatectomy (PH) was used to induce liver cell proliferation and serological and histological lipo- and glyco-metabolic perturbations were investigated in PCSK9 knockout and wild-type mice before and after PH. Mitochondrial bioenergetic level, compartmental architecture as well as intracellular localization and function of PCSK9 were further analyzed in vitro on murine primary isolated hepatocytes and PCSK9 lentiviral knockdown human liver cancer cell lines. Results Loss of PCSK9 expression led to a basal higher mitochondrial bioenergetic status in hepatocytes, characterized by a profound remodeling of mitochondrial architecture. Livers from PCSK9 knockout mice displayed a diffuse oxidative stress and a significant upregulation of cellular detoxification and superoxide radicals removal genes induced by the activation of c-Jun N-terminal kinase (JNK) pathway before PH. PCSK9 deficient mice showed a primed compensatory hepatic hyperplasia after PH, accompanied by an earlier transient regeneration-associated steatosis due to a higher LDLR expression and cholesterol uptake, with an increased β-oxidation, gluconeogenesis and glycolysis rate. Tetramethylrhodamine ethyl ester staining of isolated hepatocytes and liver cancer PCSK9 knockdown clones revealed a significantly reduced mitochondrial membrane potential when compared to controls. Confocal live-cell imaging and proteins immunoprecipitation showed respectively a mitochondrial recruitment of PCSK9 in proliferating cells and its interaction with mitochondrial membrane carriers and chaperons. Conclusion Despite the role played by circulating PCSK9 in regulating systemic cholesterol levels, our data shed light on its intracellular impact on mitochondrial architecture, membrane polarization and related metabolic perturbations in compartmental bioenergetics.

Published
2022

16. Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Author

Studer, P, primary, da Silva, C G, additional, Revuelta Cervantes, J M, additional, Mele, A, additional, Csizmadia, E, additional, Siracuse, J J, additional, Damrauer, S M, additional, Peterson, C R, additional, Candinas, D, additional, Stroka, D M, additional, Ma, A, additional, Bhasin, M, additional, and Ferran, C, additional

Published
2015
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20. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota

Author

Balmer, Ml, Slack, E, De Gottardi, A, Lawson, Mae, Hapfelmeier, S, Miele, L, Grieco, Antonio, Van Vlierberghe, H, Fahrner, R, Patuto, N, Bernsmeier, C, Ronchi, F, Wyss, M, Stroka, D, Dickgreber, N, Heim, Mh, Mccoy, Kd, Macpherson, Aj, Grieco, Antonio (ORCID:0000-0002-0544-8993), Balmer, Ml, Slack, E, De Gottardi, A, Lawson, Mae, Hapfelmeier, S, Miele, L, Grieco, Antonio, Van Vlierberghe, H, Fahrner, R, Patuto, N, Bernsmeier, C, Ronchi, F, Wyss, M, Stroka, D, Dickgreber, N, Heim, Mh, Mccoy, Kd, Macpherson, Aj, and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

A prerequisite for establishment of mutualism between the host and the microbial community that inhabits the large intestine is the stringent mucosal compartmentalization of microorganisms. Microbe-loaded dendritic cells trafficking through lymphatics are arrested at the mesenteric lymph nodes, which constitute the firewall of the intestinal lymphatic circulation. We show in different mouse models that the liver, which receives the intestinal venous blood circulation, forms a vascular firewall that captures gut commensal bacteria entering the bloodstream during intestinal pathology. Phagocytic Kupffer cells in the liver of mice clear commensals from the systemic vasculature independently of the spleen through the liver's own arterial supply. Damage to the liver firewall in mice impairs functional clearance of commensals from blood, despite heightened innate immunity, resulting in spontaneous priming of nonmucosal immune responses through increased systemic exposure to gut commensals. Systemic immune responses consistent with increased extraintestinal commensal exposure were found in humans with liver disease (nonalcoholic steatohepatitis). The liver may act as a functional vascular firewall that clears commensals that have penetrated either intestinal or systemic vascular circuits.

Published
2014

46. In vitrorescue of FGAdeletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes

Author

Stroka, D., Keogh, A., Vu, D., Fort, A., Stoffel, M.H., Kühni‐Boghenbor, K., Furer, C., Banz, V., Demarmels Biasiutti, F., Lämmle, B., Candinas, D., and Neerman‐Arbez, M.

Abstract

Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bβ and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGAhomozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality.

Published
2014
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47. Glucocorticoid-mediated repression of NFkappaB activity in endothelial cells does not involve induction of IkappaBalpha synthesis.

Author

Brostjan, C, Anrather, J, Csizmadia, V, Stroka, D, Soares, M, Bach, F H, and Winkler, H

Abstract

Repression of NFkappaB-dependent gene expression is one of the major elements of immunosuppression by glucocorticoids. Protein-protein interactions between the glucocorticoid receptor and NFkappaB have been characterized and shown to be a possible mechanism of mutual inhibition of transactivation properties. More recently, glucocorticoid-mediated induction of IkappaBalpha, an inhibitor of NFkappaB, has been described in monocytes and lymphocytes; an increase in IkappaBalpha mRNA and protein resulted in inactivation and cytosolic retention of NFkappaB. Thus, rather than the physical interaction between the glucocorticoid receptor and NFkappaB, the up-regulation of IkappaBalpha was presented as the key element in immunosuppression by glucocorticoids. In contrast, we show that the IkappaBalpha pathway is not involved in glucocorticoid-mediated inhibition of NFkappaB activity in endothelial cells. Although transcriptional activation by NFkappaB was significantly reduced in the presence of glucocorticoids, we did not detect induction of IkappaBalpha protein that could prevent nuclear translocation of NFkappaB upon stimulation with lipopolysaccharide or tumor necrosis factor alpha. Furthermore, treatment with glucocorticoids did not seem to affect the transcription rate or mRNA stability of IkappaBalpha. We therefore conclude that, although induction of IkappaBalpha expression by glucocorticoids seems to be of importance in monocytes and lymphocytes, it cannot explain inhibition of NFkappaB-dependent gene expression in endothelial cells. Our results emphasize the relevance of physical interaction between the glucocorticoid receptor and NFkappaB in endothelial cells and thus in suppression of inflammation by glucocorticoids.

Published
1996

48. A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism.

Author

Cooper, J T, Stroka, D M, Brostjan, C, Palmetshofer, A, Bach, F H, and Ferran, C

Abstract

The A20 gene product is a novel zinc finger protein originally described as a tumor necrosis factor alpha (TNF)-inducible early response gene in human umbilical vein endothelial cells (HUVEC). Its described function is to block TNF-induced apoptosis in fibroblasts and B lymphocytes, but more recently it has also been shown to play a role in lymphoid cell maturation. The mechanism of action of A20 is unknown. The aim of our study was to assess the effect of A20 upon endothelial cell activation. By transfecting bovine aortic endothelial cells (BAEC) with A20 as well as reporter constructs consisting of the promoters of genes known to be up-regulated during endothelial cell activation, i.e. E-selectin, interleukin (IL)-8, tissue factor (TF), and inhibitor of nuclear factor kappaBalpha (IkappaBalpha), we demonstrate that A20 expression inhibits gene up-regulation associated with TNF, lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), and hydrogen peroxide (H2O2)-induced endothelial cell (EC) activation. The mechanism of action of A20 is in part, or totally, due to the blockade of nuclear factor kappaB (NF-kappaB), as shown by its ability to suppress the activity of a NF-kappaB reporter. This effect is specific, as A20 does not block a noninducible, constitutively expressed reporter, Rous sarcoma virus-luciferase (RSV-LUC); nor does it block the c-Tat-inducible, NF-kappaB-independent reporter, human immunodeficiency virus-chloramphenicol acetyltransferase (HIV-CAT). How A20 blocks NF-kappaB is unclear, although we demonstrate that it does not affect p65 (RelA)-mediated gene transactivation. The inhibition of endothelial cell activation by A20 is a novel function for A20.

Published
1996

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