Dataset Information

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.

ABSTRACT:

Objective

To determine the role of hepatocyte growth factor (HGF)/c-Met on ?-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.

Research design and methods

We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced ?-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-?B.

Results

Islets exposed in vitro to cytokines or from MLDS-treated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in ?-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and ?-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for ?-cell growth and function under basal conditions. However, PancMet KO mice were more susceptible to MLDS-induced diabetes. They displayed higher blood glucose levels, marked hypoinsulinemia, and reduced ?-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and ?-cell apoptosis. c-Met-null ?-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-?B activation and NO production. Conversely, HGF treatment decreased p65/NF-?B activation and fully protected mouse and, more important, human ?-cells against cytokines.

Conclusions

These results show that HGF/c-Met is critical for ?-cell survival by attenuating NF-?B signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing ?-cell protection.

SUBMITTER: Mellado-Gil J

PROVIDER: S-EPMC3028352 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Publications

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.

Mellado-Gil Jose J Rosa Taylor C TC Demirci Cem C Gonzalez-Pertusa Jose A JA Velazquez-Garcia Silvia S Ernst Sara S Valle Shelley S Vasavada Rupangi C RC Stewart Andrew F AF Alonso Laura C LC Garcia-Ocaña Adolfo A

Diabetes 20101027 2

<h4>Objective</h4>To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.<h4>Research design and methods</h4>We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced β-cell death in mouse and human islets, ...[more]

PMID: 20980460

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Project description:TCPOBOP (1,4-Bis [2-(3,5-Dichloropyridyloxy)] benzene) is a constitutive androstane receptor (CAR) agonist that induces robust hepatocyte proliferation and hepatomegaly without any liver injury or tissue loss. TCPOBOP-induced direct hyperplasia has been considered to be CAR-dependent with no evidence of involvement of cytokines or growth factor signaling. Receptor tyrosine kinases (RTKs), MET and epidermal growth factor receptor (EGFR), are known to play a critical role in liver regeneration after partial hepatectomy, but their role in TCPOBOP-induced direct hyperplasia, not yet explored, is investigated in the current study. Disruption of the RTK-mediated signaling was achieved using MET knockout (KO) mice along with Canertinib treatment for EGFR inhibition. Combined elimination of MET and EGFR signaling [MET KO + EGFR inhibitor (EGFRi)], but not individual disruption, dramatically reduced TCPOBOP-induced hepatomegaly and hepatocyte proliferation. TCPOBOP-driven CAR activation was not altered in [MET KO + EGFRi] mice, as measured by nuclear CAR translocation and analysis of typical CAR target genes. However, TCPOBOP-induced cell cycle activation was impaired in [MET KO + EGFRi] mice due to defective induction of cyclins, which regulate cell cycle initiation and progression. TCPOBOP-driven induction of FOXM1, a key transcriptional regulator of cell cycle progression during TCPOBOP-mediated hepatocyte proliferation, was greatly attenuated in [MET KO + EGFRi] mice. Interestingly, TCPOBOP treatment caused transient decline in hepatocyte nuclear factor 4 alpha expression concomitant to proliferative response; this was not seen in [MET KO + EGFRi] mice. Transcriptomic profiling revealed the vast majority (~40%) of TCPOBOP-dependent genes primarily related to proliferative response, but not to drug metabolism, were differentially expressed in [MET KO + EGFRi] mice. Conclusion: Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP-induced proliferative response without altering CAR activation.

Dataset Information

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.

Objective

Research design and methods

Results

Conclusions

Publications

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.

Similar Datasets

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