A hepatocyte growth factor receptor (Met)−insulin receptor hybrid governs hepatic glucose metabolism

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Abstract

Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. Here we report that the HGF-Met axis regulates metabolism by stimulating hepatic glucose uptake and suppressing hepatic glucose output. We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. We also found that the HGF-Met system restores insulin responsiveness in a mouse model of insulin refractoriness. These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting.

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Figure 1: HGF-Met stimulates hepatocyte glucose uptake through crosstalk with INSR.
Figure 2: Met interacts with and phosphorylates INSR.
Figure 3: INSR activation and IRS recruitment to Met requires functional Met kinase.
Figure 4: Loss of Met function in the liver impairs glucose homeostasis.
Figure 5: HGF administration to diabetic mice dampens endogenous glucose efflux into blood.
Figure 6: Administering HGF to mice alters key gluconeogenic mediators in the liver.

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Acknowledgements

We thank G.K. Michalopoulos and S. Strom (University of Pittsburgh) for providing primary rodent and human hepatocyte cultures. We also thank A. Eaker and C. Johnson for their technical assistance. This study was supported by an R01 grant (R01NIAA001871301) awarded to R.Z. by the US National Institutes of Health.

Author information

R.Z. developed the hypothesis, designed the experimental approaches and interpreted data. A.F. and J.M. performed experiments, collected data and performed analyses. M.C.D. helped with the histological studies and data interpretation. J.L. performed the gene array studies. J.S. and X.T. performed mouse injection experiments, mouse tissue harvesting, immunohistostaining and other technical assays.

Correspondence to Reza Zarnegar.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9, Supplementary Table 1 and Supplementary Methods (PDF 1309 kb)

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