Identification and change in the receptor for hepatocyte growth factor in rat liver after partial hepatectomy or induced hepatitis

doi:10.1016/S0006-291X(05)80226-8

Biochemical and Biophysical Research Communications

Volume 176, Issue 2, 30 April 1991, Pages 599-607

https://doi.org/10.1016/S0006-291X(05)80226-8 Get rights and content

Summary

Specific binding of ¹²⁵I-labeled human recombinant HGF to the primary cultured rat hepatocytes or liver plasma membranes was observed to be temperature- and time-dependent. Scatchard analysis indicated the presence of a single class of high affinity receptors with a dissociation constant (Kd) of 24–32 pM, a value in good accord with half maximum dose for HGF activity and a receptor density of about 500–600 sites/cell. Affinity cross-linking of the receptor with ¹²⁵I-HGF revealed the HGF receptor in rat liver membranes to be a polypeptide of Mr approximately 220,000. After partial hepatectomy, specific binding of ¹²⁵I-HGF to the membranes of residual livers decreased by 60–70% between 3 and 6 h, and was scanty at 12 h after hepatectomy. After one week, the binding was recovered to the 1.7 fold level in the untreated rat liver. This rapid down-regulation of HGF receptors was also observed in plasma membranes of rat livers in the presence of hepatitis induced by CC14. We propose that HGF which can be immediately supplied to the liver after hepatic injury will function as a trigger for regeneration of this organ.

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Therefore, pharmacokinetic modeling in humans will need to be reevaluated when further information becomes available at various doses. In addition, the Kd,2 in monkeys was much higher than the reported Kd value27 for the association of HGF with c‐Met (Table 2). Nonsaturable elimination clearance (CLns) was obtained only in monkeys (Table 2).
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Hepatocyte growth factor (HGF) has been implicated in protection against several types of cell injuries. We investigated the effects of human recombinant HGF (hrHGF) on the selective neuronal cell death in the hippocampal CA1 region after transient forebrain ischemia in rats and explored the nature of the intracellular signaling pathway for the protection against this neuronal injury. hrHGF was injected continuously into the hippocampal CA1 region directly using an osmotic pump from 10 min to 72 h after the start of reperfusion. The marked increase in the number of TUNEL-positive cells found in the CA1 region after ischemia was almost completely abolished by the hrHGF treatment. Akt phosphorylation as well as IκB phosphorylation, which has been implicated in events downstream of the Akt, was not affected by hrHGF treatment. Extracellular signal-regulated kinase (ERK) phosphorylation was decreased in the CA1 region with time after ischemia. hrHGF increased or recovered ERK phosphorylation without changing the total amount of ERK protein. Immunohistochemical analysis demonstrated that phosphorylated ERK was colocalized with a neuronal nucleus marker NeuN in the hippocampal CA1 region of ischemic rats with hrHGF treatment at the early period after reperfusion. These results suggest that the protective effects of hrHGF against neuronal death in the hippocampal CA1 after transient forebrain ischemia could be related to an ERK-dependent pathway.
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This study was done for investigation of the DNA synthesis induced by HGF/SF and EGF in periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) isolated at different times post-hepatectomy. Preparation, culture, and DNA synthesis of PPH and PVH were done as previously described. In both PPH and PVH isolated at 6 and 12 h post-hepatectomy, the maximum DNA synthesis induced by both HGF/SF and EGF was observed from 24 to 48 h post-hepatectomy. In contrast, in both types of hepatocytes isolated at 36, 72 and 96 h, 1 and 2 weeks, and 1 month post-hepatectomy, maximum DNA synthesis was observed from 48 to 72 h. However, maximum DNA synthesis induced by HGF/SF and EGF was at its lowest in PPH isolated at 12 h and PVH isolated at 6 h post-hepatectomy. Maximum DNA synthesis returned to the control level in PPH and PVH isolated at 72 and 96 h post-hepatectomy, respectively. Specific binding studies using [ $^{125} I$ ] HGF/SF and [ $^{125} I$ ] EGF supported the above data. From these data, it was demonstrated that first, the PPH and PVH cell cycles have the same post-hepatectomy, but are dependent on the preparation time. Secondly, differences in DNA synthesis in PPH and PVH post-hepatectomy suggest that liver regeneration may occur unevenly.
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Citation Excerpt :
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Identification and change in the receptor for hepatocyte growth factor in rat liver after partial hepatectomy or induced hepatitis

Summary

Biochem. Biophys. Res. Commun.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Methods. Cell. Biol.

Exp. Cell. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Commun.

Int. J. Biochem.