Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes

Senn, Joseph J.; Klover, Peter; Nowak, Irena; Zimmers, Teresa A.; Koniaris, Leonidas G.; Furlanetto, Richard W.; Mooney, Robert A.

doi:10.1074/jbc.m210689200

Cited by 544 publications

(438 citation statements)

References 57 publications

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“…In addition, SOCS3 inhibits insulin signalling as shown both in vitro and in animal models [35][36][37]. As reported previously, in this study IL-6 upregulated SOCS3 mRNA in HepG2 cells with the peak at 1 h post-induction [35] (Fig. 5c).…”

Section: Ilsupporting

confidence: 87%

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

et al. 2010

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Aim/hypothesis The aim of the study was to examine the possible role of AMP-activated protein kinase (AMPK) in the regulation of the inflammatory response induced by cytokine action in human liver cells. Methods IL-6-stimulated expression of the genes for acutephase response markers serum amyloid A (SAA1, SAA2) and haptoglobin (HP) in the human hepatocarcinoma cell line HepG2 were quantified after modulation of AMPK activity by pharmacological agonists (5-amino-4-imidazolecarboxamideriboside [AICAR], metformin) or by using small interfering (si) RNA transfection. The intracellular signalling pathway mediating the effect of AMPK on IL-6-stimulated acute-phase marker expression was characterised by assessing the phosphorylation levels of the candidate protein signal transducer and activator of transcription 3 (STAT3) in response to AMPK agonists. Results AICAR and metformin markedly blunt the IL-6-stimulated expression of SAA cluster genes as well as of haptoglobin in a dose-dependent manner. Moreover, the repression of AMPK activity by siRNA significantly reversed the inhibition of SAA expression by both AICAR and metformin, indicating that the effect of the agonists is dependent on AMPK. For the first time we show that AMPK appears to regulate IL-6 signalling by directly inhibiting the activation of the main downstream target of IL-6, STAT3. Conclusions/interpretation We provide evidence for a key function of AMPK in suppression of the acute-phase response caused by the action of IL-6 in liver, suggesting that AMPK may act as an intracellular link between chronic low-grade inflammation and metabolic regulation in peripheral metabolic tissues.

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Section: Ilsupporting

confidence: 87%

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

et al. 2010

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“…Many studies have analysed this question, and these will only be summarised here. Immune mediators such as TNF-α and IL-6 can directly interfere with insulin signalling [99][100][101][102][103], and the binding of these cytokines to their cognate receptor on muscle cells or hepatocytes has been shown to induce an intracellular response that interferes with the ability of the insulin receptor to phosphorylate its intracellular targets. The cellular response to insulin is dampened in consequence.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

“…One well-described example of this is the induction of the protein suppressor of cytokine signalling-3 (SOCS-3) by IL-6 in hepatocytes. This protein associates with the insulin receptor and suppresses insulindependent receptor autophosporylation and IRS-1 phosphorylation [100]. SOCS-3 also binds to IRS-1 and IRS-2, leading to their ubiquitination and proteasomal degradation [104].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

An immune origin of type 2 diabetes?

2005

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Subclinical, low-grade systemic inflammation has been observed in patients with type 2 diabetes and in those at increased risk of the disease. This may be more than an epiphenomenon. Alleles of genes encoding immune/ inflammatory mediators are associated with the disease, and the two major environmental factors the contribute to the risk of type 2 diabetes-diet and physical activity-have a direct impact on levels of systemic immune mediators. In animal models, targeting of immune genes enhanced or suppressed the development of obesity or diabetes. Obesity is associated with the infiltration and proinflammatory activity of macrophages in adipose tissue, and immune mediators may be important regulators of insulin resistance, mitochondrial function, ectopic lipid storage and beta cell dysfunction or death. Intervention studies targeting these pathways would help to determine the contribution of an activated innate immune system to the development of type 2 diabetes.

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“…Several reports have demonstrated that ectopic expression of SOCS3 may lead to insulin resistance (Senn et al 2003;Steppan et al 2005;Ye et al 2012;Jorgensen et al 2013). As shown in Fig.…”

Section: Discussionmentioning

confidence: 93%

“…SOCS3 is a member of the suppressors of cytokine signaling (SOCS) family, which is a recently discovered family of proteins associated with the inhibition of insulin receptor signaling (Senn et al 2003). Several reports have demonstrated that ectopic expression of SOCS3 may lead to insulin resistance (Senn et al 2003;Steppan et al 2005;Ye et al 2012;Jorgensen et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

Song¹,

Wang²,

Mao³

et al. 2013

Gene

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The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P<0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggests that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin

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Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes

Abstract: Interleukin-6 (IL-6

Cited by 544 publications

References 57 publications

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

An immune origin of type 2 diabetes?

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

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