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Hepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levelsMatz-Soja, Madlen, Gebhardt, Rolf 06 May 2014 (has links) (PDF)
Background
Hedgehog signaling plays an important role in embryonic development, organogenesis and cancer. In the adult liver, Hedgehog signaling in non-parenchymal cells has been found to play a role in certain disease states such as fibrosis and cirrhosis. However, whether the Hedgehog pathway is active in mature healthy hepatocytes and is of significance to liver function are controversial.
Findings
Two types of mice with distinct conditional hepatic deletion of the Smoothened gene, an essential co-receptor protein of the Hedgehog pathway, were generated for investigating the role of Hedgehog signaling in mature hepatocytes. The knockout animals (KO) were inconspicuous and healthy with no changes in serum transaminases, but showed a slower weight gain. The liver was smaller, but presented a normal architecture and cellular composition. By quantitative RT-PCR the downregulation of the expression of Indian hedgehog (Ihh) and the Gli3 transcription factor could be demonstrated in healthy mature hepatocytes from these mice, whereas Patched1 was upregulated. Strong alterations in gene expression were also observed for the IGF axis. While expression of Igf1 was downregulated, that of Igfbp1 was upregulated in the livers of both genders. Corresponding changes in the serum levels of both proteins could be detected by ELISA. By activating and inhibiting the transcriptional output of Hedgehog signaling in cultured hepatocytes through siRNAs against Ptch1 and Gli3, respectively, in combination with a ChIP assay evidence was collected indicating that Igf1 expression is directly dependent on the activator function of Gli3. In contrast, the mRNA level of Igfbp1 appears to be controlled through the repressor function of Gli3, while that of Igfbp2 and Igfbp3 did not change. Interestingly, body weight of the transgenic mice correlated well with IGF-I levels in both genders and also with IGFBP-1 levels in females, whereas it did not correlate with serum growth hormone levels.
Conclusions
Our results demonstrate for the first time that Hedgehog signaling is active in healthy mature mouse hepatocytes and that it has considerable importance for IGF-I homeostasis in the circulation. These findings may have various implications for mouse physiology including the regulation of body weight and size, glucose homeostasis and reproductive capacity.
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Resveratrol Differentially Regulates NAMPT and SIRT1 in Hepatocarcinoma Cells and Primary Human HepatocytesSchuster, Susanne, Garten, Antje 07 May 2014 (has links) (PDF)
Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate
the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on
NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells)
and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in
hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in
hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and
apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol
treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol
induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was
absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by
EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53
hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that
NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that
resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells.
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Hepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levelsMatz-Soja, Madlen, Gebhardt, Rolf January 2014 (has links)
Background
Hedgehog signaling plays an important role in embryonic development, organogenesis and cancer. In the adult liver, Hedgehog signaling in non-parenchymal cells has been found to play a role in certain disease states such as fibrosis and cirrhosis. However, whether the Hedgehog pathway is active in mature healthy hepatocytes and is of significance to liver function are controversial.
Findings
Two types of mice with distinct conditional hepatic deletion of the Smoothened gene, an essential co-receptor protein of the Hedgehog pathway, were generated for investigating the role of Hedgehog signaling in mature hepatocytes. The knockout animals (KO) were inconspicuous and healthy with no changes in serum transaminases, but showed a slower weight gain. The liver was smaller, but presented a normal architecture and cellular composition. By quantitative RT-PCR the downregulation of the expression of Indian hedgehog (Ihh) and the Gli3 transcription factor could be demonstrated in healthy mature hepatocytes from these mice, whereas Patched1 was upregulated. Strong alterations in gene expression were also observed for the IGF axis. While expression of Igf1 was downregulated, that of Igfbp1 was upregulated in the livers of both genders. Corresponding changes in the serum levels of both proteins could be detected by ELISA. By activating and inhibiting the transcriptional output of Hedgehog signaling in cultured hepatocytes through siRNAs against Ptch1 and Gli3, respectively, in combination with a ChIP assay evidence was collected indicating that Igf1 expression is directly dependent on the activator function of Gli3. In contrast, the mRNA level of Igfbp1 appears to be controlled through the repressor function of Gli3, while that of Igfbp2 and Igfbp3 did not change. Interestingly, body weight of the transgenic mice correlated well with IGF-I levels in both genders and also with IGFBP-1 levels in females, whereas it did not correlate with serum growth hormone levels.
Conclusions
Our results demonstrate for the first time that Hedgehog signaling is active in healthy mature mouse hepatocytes and that it has considerable importance for IGF-I homeostasis in the circulation. These findings may have various implications for mouse physiology including the regulation of body weight and size, glucose homeostasis and reproductive capacity.
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Resveratrol Differentially Regulates NAMPT and SIRT1 in Hepatocarcinoma Cells and Primary Human Hepatocytes: Resveratrol Differentially Regulates NAMPT and SIRT1 inHepatocarcinoma Cells and Primary Human HepatocytesSchuster, Susanne, Garten, Antje January 2014 (has links)
Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate
the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on
NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells)
and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in
hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in
hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and
apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol
treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol
induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was
absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by
EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53
hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that
NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that
resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells.
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UPSTREAM PATHWAYS REGULATING ERYTHROPOIETIN GENE EXPRESSION IN THE LIVER DURING ACUTE PHASE RESPONSE: A CENTRAL ROLE FOR IL-6. / ERYTHROPOIETIN GENE EXPRESSION IN TWO MURINE MODELS OF APR. / Vorgeschaltete Stoffwechselwege regulieren die Erythropoietin-Genexpression in der Leber während der Akute-Phase-Antwort: Eine zentrale Rolle für IL-6 / Erythropoietin-Genexpression in zwei modellen der Akute-Phase ReaktionRamadori, Pierluigi 22 April 2010 (has links)
No description available.
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De novo Induktion von Anaphylatoxin C5a-Rezeptoren in Hepatocyten der Ratte durch den Entzündungsauslöser Lipopolysaccharid in vivo / Vermittlung durch die Entzündungsmediatoren Interleukin-6 und -1ß / De novo induction of anaphylatoxin C5aR in rat hepatocytes by bacterial lipopolysaccharide in vivo / Mediation by the proinflammatory cytokines interleukine-6 and -1ßKoleva, Milena 03 May 2001 (has links)
No description available.
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