PMID- 22178588
OWN - NLM
STAT- MEDLINE
DCOM- 20120531
LR  - 20220310
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 142
IP  - 4
DP  - 2012 Apr
TI  - Protein engineered variants of hepatocyte growth factor/scatter factor promote 
      proliferation of primary human hepatocytes and in rodent liver.
PG  - 897-906
LID - 10.1053/j.gastro.2011.12.006 [doi]
AB  - BACKGROUND & AIMS: Hepatocyte growth factor/scatter factor (HGF/SF) stimulates 
      hepatocyte DNA synthesis and protects against apoptosis; in vivo it promotes 
      liver regeneration and reduces fibrosis. However, its therapeutic value is 
      limited by its complex domain structure, high cost of production, instability, 
      and poor tissue penetration due to sequestration by heparin sulfate proteoglycans 
      (HSPGs). METHODS: Using protein engineering techniques, we created a full-length 
      form of HGF/SF (called HP21) and a form of the small, naturally occurring HGF/SF 
      fragment, NK1 (called 1K1), which have reduced affinity for HSPG. We 
      characterized the stability and proliferative and anti-apoptotic effects of these 
      variants in primary human hepatocytes and in rodents. RESULTS: Analytical 
      ultracentrifugation showed that 1K1 and NK1 were more stable than the native, 
      full-length protein. All 4 forms of HGF/SF induced similar levels of DNA 
      synthesis in human hepatocytes; 1K1 and NK1 required heparin, an HSPG analogue, 
      for full agonistic activity. All the proteins reduced levels of Fas 
      ligand-mediated apoptosis, reducing the activity of caspase-3/7 and cleavage of 
      poly(adenosine diphosphate-ribose) polymerase. 1K1 was more active than NK1 in 
      rodents; in healthy mice, 1K1 significantly increased hepatocyte DNA synthesis, 
      and in mice receiving carbon tetrachloride, it reduced fibrosis. In rats, after 
      70% partial hepatectomy, daily administration of 1K1 for 5 days significantly 
      increased liver mass and the bromodeoxyuridine labeling index compared with mice 
      given NK1. CONCLUSIONS: 1K1, an engineered form of the small, naturally occurring 
      HGF/SF fragment NK1, has reduced affinity for HSPG and exerts proliferative and 
      antiapoptotic effects in cultured hepatocytes. In rodents, 1K1 has antifibrotic 
      effects and promotes liver regeneration. The protein has better stability and is 
      easier to produce than HGF/SF and might be developed as a therapeutic for acute 
      and chronic liver disease.
CI  - Copyright (c) 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Ross, Jacob
AU  - Ross J
AD  - UCL Hepatology, Royal Free Campus, University College London, London, England, 
      UK.
FAU - Gherardi, Ermanno
AU  - Gherardi E
FAU - Mallorqui-Fernandez, Noemi
AU  - Mallorqui-Fernandez N
FAU - Bocci, Marco
AU  - Bocci M
FAU - Sobkowicz, Anna
AU  - Sobkowicz A
FAU - Rees, Myrrdin
AU  - Rees M
FAU - Rowe, Arthur
AU  - Rowe A
FAU - Ellmerich, Stephan
AU  - Ellmerich S
FAU - Massie, Isobel
AU  - Massie I
FAU - Soeda, Junpei
AU  - Soeda J
FAU - Selden, Clare
AU  - Selden C
FAU - Hodgson, Humphrey
AU  - Hodgson H
LA  - eng
GR  - G9704528/MRC_/Medical Research Council/United Kingdom
GR  - 2291:081377/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111213
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Fas Ligand Protein)
RN  - 0 (HGF protein, human)
RN  - 0 (Heparan Sulfate Proteoglycans)
RN  - 0 (Peptide Fragments)
RN  - 0 (Recombinant Proteins)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 7)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Binding Sites
MH  - Carbon Tetrachloride
MH  - Caspase 3/metabolism
MH  - Caspase 7/metabolism
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - DNA Replication
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Fas Ligand Protein/metabolism
MH  - Heparan Sulfate Proteoglycans/metabolism
MH  - Hepatectomy
MH  - Hepatocyte Growth Factor/chemistry/genetics/metabolism/*pharmacology
MH  - Hepatocytes/*drug effects/metabolism/pathology
MH  - Humans
MH  - Liver/*drug effects/metabolism/pathology/surgery
MH  - Liver Cirrhosis/chemically induced/metabolism/pathology/*prevention & control
MH  - Liver Regeneration/*drug effects
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Models, Molecular
MH  - Peptide Fragments/chemistry/genetics/metabolism/*pharmacology
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Protein Conformation
MH  - *Protein Engineering
MH  - Protein Stability
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins/metabolism
MH  - Time Factors
MH  - Ultracentrifugation
EDAT- 2011/12/20 06:00
MHDA- 2012/06/01 06:00
CRDT- 2011/12/20 06:00
PHST- 2011/09/07 00:00 [received]
PHST- 2011/11/11 00:00 [revised]
PHST- 2011/12/01 00:00 [accepted]
PHST- 2011/12/20 06:00 [entrez]
PHST- 2011/12/20 06:00 [pubmed]
PHST- 2012/06/01 06:00 [medline]
AID - S0016-5085(11)01663-5 [pii]
AID - 10.1053/j.gastro.2011.12.006 [doi]
PST - ppublish
SO  - Gastroenterology. 2012 Apr;142(4):897-906. doi: 10.1053/j.gastro.2011.12.006. 
      Epub 2011 Dec 13.