Heterogeneous expression of suppressor of cytokine signalling 2 (SOCS‐2) in liver tissue

Zellmer, Sebastian; Sickinger, Stephan; Schmidt‐Heck, Wolfgang; Guthke, Reinhard; Gebhardt, Rolf

doi:10.1111/j.1469-7580.2009.01085.x

Cited by 9 publications

(11 citation statements)

References 35 publications

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“…We demonstrate this directly. SOCS2 was previously shown to be preferentially expressed in the pericentral regions of the liver, also consistent with our data (25). Normal expression of GH in the pituitary of Socs2-null mice is consistent with previous findings.…”

Section: Discussionsupporting

confidence: 93%

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

Masuzaki

Zhao

Valerius

et al. 2016

Journal of Biological Chemistry

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After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.Control of liver regeneration requires both stimulatory and inhibitory factors (1-11). Although it might be expected that stimulatory factors are induced and inhibitory factors repressed after partial hepatectomy, in fact, for certain genes, the reverse occurs. For example, suppressor of cytokine signaling 3 (SOCS3), 2 an inhibitor of liver regeneration, is induced after partial hepatectomy (2). This observation raises the possibility that mechanisms exist to limit the rate of liver regeneration after injury. What is the reason for this? One possible explanation considers that metabolic activity may be impaired in proliferating compared with non-proliferating hepatocytes. If true, after severe injury liver regeneration might need to be limited to a rate that balances the acute need to maintain the diverse functions of the liver and prevent the death of the organism with the long-term need for hepatocytes to proliferate to restore mass and maximum functional capacity.Growth hormone (GH) signaling plays a central role in liver regeneration and may provide clues to how the rate of hepatocyte proliferation after injury is precisely regulated. Mice lacking GH activity display a diminished response to hepatectomy and do not restore liver mass even 7 days after partial hepatectomy (12). Loss of growth hormone receptor (GHR) impairs liver regeneration, and mice lacking Stat5, a transducer of GH signaling, demonstrate impaired hepatocyte proliferation after partial hepatectomy (13,14).GH is produced in the pituitary, stored in granules, and released into the circulation in response to growth hormone releasing hormone. This process is inhibited by a number of factors, including insulin-like growth factor 1 (IGF-1), which is produced primarily in the liver, and somatostatin (15).In target tissues, GH binds to the GHR and modulates phosphorylation of important intracellular messengers including JAK2, signal transdu...

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Section: Discussionsupporting

confidence: 93%

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

Masuzaki

Zhao

Valerius

et al. 2016

Journal of Biological Chemistry

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“…Immunohistochemistry on paraffin sections (3 µm) was performed as previously described ( Zellmer et al, 2009 ). The sections were boiled (3 × 5 min) in buffer (0.01 M sodium citrate, pH 6.0) and the slides were incubated for 30 min in 5% goat serum (Sigma-Aldrich, Germany) to block nonspecific binding.…”

Section: Methodsmentioning

confidence: 99%

“…The following antibodies were used: rabbit anti-FAS (1:400, Cell Signaling Technology, USA), rabbit anti-Cre (1:4000; Abcam, Cambridge), anti-GLI3 (1:1000; GeneTex, USA), anti-GLI1 (1:1000; GeneTex, USA), anti-SREBP1 (1:200; Abcam, Cambridge) anti-PPARG (1:250, ThermoFisher Scientific, Germany), biotinylated goat anti-rabbit IgG (Millipore, Germany) and Extravidine (Sigma-Aldrich, Germany). POD and counterstaining with hematoxylin were performed as previously described ( Zellmer et al, 2009 ).…”

Section: Methodsmentioning

confidence: 99%

“…Microarray analysis was conducted using isolated hepatocytes from four independent SLC-WT and four SLC-KO mice, at the microarray core facility of the Interdisziplinäres Zentrum für klinische Forschung (IZKF) Leipzig (Faculty of Medicine, Leipzig University) described by Zellmer et al ( Zellmer et al, 2009 ). Briefly, GeneChip Mouse Genome 430 2.0 Arrays (Affymetrix) were used for hybridization.…”

Section: Methodsmentioning

confidence: 99%

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Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

Matz‐Soja

Rennert

Schönefeld

et al. 2016

eLife

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Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.DOI: http://dx.doi.org/10.7554/eLife.13308.001

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“…Previous studies in mice have documented that SOCS proteins significantly increased in glomeruli and tubulointerstitium parallel with proteinuria and renal lesions during immune renal injury (Gomez-Guerrero, 2004). SOCS-2 expression was found to be heterogeneously expressed in murine liver parenchyma (Zellmer, 2009). …”

Section: Discussionmentioning

confidence: 95%

Effect of Anaphylactic Shock on Suppressors of Cytokine Signaling

Liang

Tang

et al. 2010

Immunological Investigations

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The pathophysiologic mechanisms of anaphylactic shock still remain unclear. In this study, we investigated the changes of expression and translation of SOCS1/SOCS3 in the heart, lungs, kidney, liver and spleen from patients who died of anaphylactic shock. Samples from the same viscera of 8 patients who died of anaphylactic shock and 8 healthy controls who died from accidents were collected in the present study. The level of IgE was measured in heart, and SOCS1/ SOCS3 mRNA and protein expression were determined by RT-PCR and immunohistochemistry, respectively. As a result, the higher IgE level was detected in the blood samples from the patients' heart than the control. SOCS1 and SOCS3 protein were significantly increased in the kidney and liver than the control. After anaphylactic shock, the expression of SOCS1 and SOCS3 mRNA were also increased. The expression level of SOCS3 mRNA was higher than that of SOCS1 in all viscera, and both were the highest in liver and kidney. There was a positive correlation between SOCS1 mRNA and SOCS3 mRNA in liver and kidney after anaphylactic shock. Our results indicate that SOCS1 and SOCS3 may play a regulatory role in anaphylactic shock viscera injury processes during anaphylactic shock.

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Heterogeneous expression of suppressor of cytokine signalling 2 (SOCS‐2) in liver tissue

Cited by 9 publications

References 35 publications

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

Effect of Anaphylactic Shock on Suppressors of Cytokine Signaling

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