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See detailThe role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells.
Battello, Nadia UL; Zimmer, Andreas David UL; Goebel, Carole et al

in Cancer & metabolism (2016), 4

BACKGROUND: Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver ... [more ▼]

BACKGROUND: Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver cancer development is promoted by an inflammatory microenvironment. The inflammatory cytokine oncostatin M (OSM) was shown to induce the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) under normoxic conditions in hepatocytes and hepatoma cells. HIF-1 alpha is known to orchestrate the expression of numerous genes, many of which code for metabolic enzymes that play key roles in the adaptation of cellular metabolism to low oxygen tension. RESULTS: Here, we show that OSM-induced upregulation of HIF-1 alpha reprograms cellular metabolism in three clones of the human hepatocyte cell line PH5CH (PH5CH1, PH5CH7, and PH5CH8) towards a hypoxia-like metabolic phenotype but has no significant effect on cellular metabolism of HepG2 and JHH-4 hepatoma cells. Although we observed only minor changes in glucose uptake and lactate secretion in PH5CH8 upon OSM treatment, we identified more pronounced changes in intracellular fluxes based on stable isotope labeling experiments. In particular, glucose oxidation in the tricarboxylic acid (TCA) cycle is reduced through pyruvate dehydrogenase kinase 1 (PDK1)-mediated inhibition of the pyruvate dehydrogenase complex, thereby reducing the oxidative TCA cycle flux. As a result of the impaired mitochondrial glucose and glutamine oxidation, the reductive isocitrate dehydrogenase flux was increased. CONCLUSIONS: We provide evidence that connects the inflammatory mediator OSM to a hypoxia-like metabolic phenotype. In the human hepatocyte cell line PH5CH, OSM-mediated upregulation of HIF-1 alpha and PDK1 can induce hypoxia-like metabolic changes, although to a lesser extent than hypoxia itself. Since PDK1 is overexpressed in several cancers, it might provide a causal link between chronic inflammation and malignant cellular transformation. [less ▲]

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See detailCyclooxygenase-2 contributes to the selective induction of cell death by the endocannabinoid 2-arachidonoyl glycerol in hepatic stellate cells.
Siegmund, S. V.; Wojtalla, A.; Schlosser, M. et al

in Biochemical and biophysical research communications (2016), 470(3), 678-84

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular ... [more ▼]

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2alpha-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2(-/-) mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2(-/-) HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis. [less ▲]

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See detailDIFFERENTIAL EFFECTS OF IL-6-TYPE CYTOKINES, THEIR INTERPLAY WITH HYPOXIA AND RESULTING EFFECTS ON THE METABOLISM
Zimmer, Andreas David UL

Doctoral thesis (2015)

IL-6-type cytokines signal mainly via the Jak/STAT pathway using the common receptor chain gp130. They are implicated in various biological processes such as differentiation, apoptosis, tissue ... [more ▼]

IL-6-type cytokines signal mainly via the Jak/STAT pathway using the common receptor chain gp130. They are implicated in various biological processes such as differentiation, apoptosis, tissue regeneration and proliferation. However, one of their main functions is the regulation of inflammatory processes, especially the initial induction of an inflammatory response. They hereby exert key steps in the onset as well as in the termination of an inflammation and in the promotion of the shift from the innate to the adaptive immune response. In hepatocellular carcinoma (HCC) IL-6 has been identified as a key factor in the onset as well as in the progression of this cancer. In this study we first investigated the effects of the IL-6-type cytokine IL-27 on hepatic cells. By evaluating IL-27 signalling in several HCC cell lines as well as hepatic cells, we could demonstrate that IL-27 does, in contrary to other IL-6-type cytokines, activate STAT1 and STAT3. A transcriptional and protein read-out of STAT3 was not found in hepatic cells. Thus, IL-27 exerts interferon γ-like functions only in the liver. Interestingly, we could further show that the IL-27 signalling can still be repressed by the canonical IL-6-type cytokine feedback regulator SOCS3, following a pre-stimulation with other IL-6-type cytokines. The second part of this thesis focused on the effects of the IL-6-type cytokine Oncostatin M (OSM) on the cellular metabolism. We hereby evaluated to which extent OSM-mediated STAT3 activation can induce a Warburg-like, highly glycolytic, metabolic phenotype under normoxia. OSM induced the expression of HIF-1α, a key factor mediating the shift to a highly glycolytic phenotype, in several HCC cell lines and immortalized hepatocytes. In the non-neoplastic hepatocyte cell line, PH5CH8, this led to the induction of a more glycolytic metabolic phenotype. The observed changes in these immortalized hepatocytes did not fully resemble the metabolic state seen under hypoxia, since mainly the observed induction of PDK1 seems to explain the effect. Overall we could not observe strong effects on glycolytic enzymes or other canonical HIF-1α target genes involved in metabolism, on a transcriptional or protein expression level in the investigated cells. Interestingly we found that HIF-1α does not seem to be mediating all the early adaptions of the cellular metabolism to hypoxia. The early inhibition of the pyruvate dehydrogenase complex could be shown to be independent of the HIF-1α-mediated up-regulation of the pyruvate dehydrogenase kinase 1, but might rather be induced by reactive oxygen species, created during the switch from normoxia to hypoxia. In summary we could show that in the liver IL-27 exerts interferon γ-like effects. Additionally, cytokine-activated STAT3 does not per se induce a glycolytic metabolic phenotype and HIF-1α is not necessary for some of the early adaptions of the cellular metabolism to hypoxia. [less ▲]

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See detailCK2 phosphorylation of C/EBPdelta regulates its transcription factor activity.
Schwind, Lisa; Zimmer, Andreas David UL; Gotz, Claudia et al

in The international journal of biochemistry & cell biology (2015), 61

Protein kinase CK2 plays an essential role in cell viability in lower and higher eukaryotes. As a global regulator it phosphorylates and thereby regulates a broad array of cellular targets including a ... [more ▼]

Protein kinase CK2 plays an essential role in cell viability in lower and higher eukaryotes. As a global regulator it phosphorylates and thereby regulates a broad array of cellular targets including a large number of transcription factors. Here, we have identified the CCAAT/enhancer binding protein delta (C/EBPdelta) as a new substrate for CK2. Using point mutants of C/EBPdelta the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPdelta. For proper functioning as a transcription factor C/EBPdelta has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPdelta nor its interaction with C/EBPbeta, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPdelta. Moreover, we found that CK2 bound to C/EBPdelta, which might help to target CK2 to the transcriptional machinery where it can phosphorylate other transcription factors or co-activators. [less ▲]

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See detailSequence interpretation. Functional annotation of mouse genome sequences.
Nadeau, J. H.; Balling, Rudi UL; Barsh, G. et al

in Science (2001), 291(5507), 1251-5

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See detailGenome-wide, large-scale production of mutant mice by ENU mutagenesis.
Hrabe de Angelis, M. H.; Flaswinkel, H.; Fuchs, H. et al

in Nature Genetics (2000), 25(4), 444-7

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model ... [more ▼]

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html). [less ▲]

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