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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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.
The authors declare no competing financial interests.
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Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells Via Hepatocyte Growth Factor/c‐Met Signaling in Obesity‐Associated Kidney Injury
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