Factor VIIa binding and internalization in hepatocytes.

Gertrud Malene Hjortø, Brit Binow Sørensen, Lars Christian Petersen, L. Vijaya Mohan Rao

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The liver is believed to be the primary clearance organ for coagulation proteases, including factor
VIIa. However, at present, clearance mechanisms for FVIIa in liver are unknown. To obtain
information on the FVIIa clearance mechanism, we investigated the binding and internalization of
FVIIa in liver cells using a human hepatoma cell line (HEPG2), and primary rat and human
hepatocytes as cell models. 125I-FVIIa bound to HEPG2 cells in a time-and dose- dependent manner.
Anti-tissue factor antibodies reduced the binding by about 25%, whereas 50-fold molar excess of
unlabeled FVIIa had no effect. HEPG2 cells internalized FVIIa with a rate of 10 fmoles/105 cells/h.
In contrast to HEPG2 cells, FVIIa binding to primary rat hepatocytes was completely independent
of TF, and excess unlabeled FVIIa partly reduced the binding of 125I-FVIIa to rat hepatocytes.
Further, compared to HEPG2 cells, 3 to 4- fold more FVIIa bound to rat primary hepatocytes, and
the bound FVIIa was internalized at a faster rate. Similar FVIIa binding and internalization profiles
were observed in primary human hepatocytes. Plasma inhibitors had no effect on FVIIa binding and
internalization in hepatocytes. In contrast, annexin V, which binds to phosphatidylserine, blocked
the binding and internalization. Consistent with this, binding of gla-domain-deleted FVIIa to
hepatocytes was markedly diminished. In summary, the data presented herein reveal differences
between HEPG2 cells and primary liver cells in FVIIa binding and internalization, and suggest that
the rapid turnover of membrane and not a receptor-mediated endocytosis may be responsible for
internalization of FVII/FVIIa in primary hepatocytes.
Original languageEnglish
JournalJournal of Thrombosis and Haemostasis
Issue number10
Pages (from-to)2264–2273
Publication statusPublished - 2005
Externally publishedYes


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