Activation of Downstream Signals by the Long Form of the Leptin Receptor

Banks, Alexander S.; Davis, Sarah M.; Bates, Sarah H.; Myers, Martin G.

doi:10.1074/jbc.275.19.14563

Cited by 698 publications

(700 citation statements)

References 68 publications

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“…The effect of this IL-6 resistance is obvious in db/db mice because these mice lack Ob-Rb, which is required for leptin-induced phosphorylation of STAT3 at Tyr 705 (see ref. 31,32). In this study, we used MR16-1 and found that this treatment had little effect on hepatic steatosis but induced greater liver injury and fibrosis in MCD diettreated db/db mice, compared with control treatment.…”

Section: Discussionmentioning

confidence: 97%

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Yamaguchi

Itoh

Yokomizo

et al. 2011

Laboratory Investigation

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Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3 À/À or GP130 À/À mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD dietfed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.

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Section: Discussionmentioning

confidence: 97%

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Yamaguchi

Itoh

Yokomizo

et al. 2011

Laboratory Investigation

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“…As a first step, we used the leptin receptor signaling as a model system. The leptin receptor is regulated by in part by SOCS3 and the single binding sites for both STAT3 (Y1138) and SOCS3 (Y985) have been defined (38,39). We expressed the leptin receptor cytoplasmic domain fused to the extracellular domain of the EpoR (ELR) (Fig.…”

Section: Leptin Receptor Signaling Activates An Airmentioning

confidence: 99%

General Nature of the STAT3-Activated Anti-Inflammatory Response

Kasmi

Holst²,

Coffre

et al. 2006

The Journal of Immunology

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201

179

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Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.

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“…10). The phosphorylated Tyr-1141 binds STAT3 from the cytosol, which becomes activated by JAK2 (32,33,57,58). The activated STAT protein translocates to the nucleus to stimulate transcription of early response genes and late target genes, including, among others, TIMP-1 gene (67, 68).…”

Section: Timp-1 Induction By Leptinmentioning

confidence: 99%

“…But leptin can also use other signaling cascades via JAK activation. Among these are p38 (31), extracellular signal-regulated kinase (ERK1/2) (2,(31)(32)(33)(34)(35)(36), and c-Jun terminal/stressactivated protein kinases (37) of the mitogen-activated protein kinase (MAPK) family members. Furthermore, leptin was found to generate increased amounts of H 2 O 2 in isolated vascular endothelial cells in association with atherogenic processes (37,38).…”

mentioning

confidence: 99%

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

Cao

Mak

Ren

et al. 2004

Journal of Biological Chemistry

154

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Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2. Leptin stimulated TIMP-1 protein, mRNA, and promoter activity. JAK1 and -2, as well as STAT3 and -5, were activated. After leptin, there was increased expression of tyrosine 1141-phosphorylated leptin receptor, which may contribute to STAT3 activation. AG 490, a JAK inhibitor, blocked JAK phosphorylation with concomitant inhibition of STAT activation, TIMP-1 mRNA expression, and promoter activity. Leptin also induced an oxidative stress, which was inhibited by AG 490, indicating a JAK mediation process. ERK1/2 MAPK and p38 were activated, which was prevented by catalase, indicating an H 2 O 2 -dependent mechanism. Catalase treatment resulted in total suppression of TIMP-1 mRNA expression and promoter activity. SB203580, a p38 inhibitor, prevented p38 activation and reduced TIMP-1 message half-life with down-regulation of TIMP-1 mRNA. These changes were reproduced by overexpression of the dominant negative p38␣ and p38␤ mutants. PD098059, an ERK1/2 inhibitor, opposed ERK1/2 activation and TIMP-1 promoter activity, leading to TIMP-1 mRNA down-regulation. Thus, leptin has a direct action on liver fibrogenesis by stimulating TIMP-1 production in activated HSC. This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H 2 O 2 -dependent p38 and ERK1/2 pathways via activated JAK.

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Activation of Downstream Signals by the Long Form of the Leptin Receptor

Cited by 698 publications

References 68 publications

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

General Nature of the STAT3-Activated Anti-Inflammatory Response

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

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