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. 1993 May;91(5):2244–2252. doi: 10.1172/JCI116451

Cell-specific expression of hepatocyte growth factor in liver. Upregulation in sinusoidal endothelial cells after carbon tetrachloride.

J J Maher 1
PMCID: PMC288227  PMID: 7683700

Abstract

The cellular origin of hepatocyte growth factor (HGF), a polypeptide implicated in liver regeneration, was examined in normal liver and in hepatic regeneration induced by carbon tetrachloride. In normal liver, HGF and its mRNA were abundant in lipocytes, with smaller amounts present also in sinusoidal endothelial and Kupffer cells. In regenerating liver, HGF gene expression increased exclusively in endothelial cells. HGF mRNA levels rose sixfold in these cells, peaking at 6 h after toxin administration and returning to near normal by 24 h. The rise in HGF mRNA was accompanied by a 5.4-fold increase in HGF secretion. CCl4 did not alter HGF expression by either Kupffer cells or lipocytes; nor did it induce HGF expression by hepatocytes. Nonparenchymal liver cells contained two HGF transcripts: one predicting a full-length molecule of 728 amino acids; and the other encoding a functional five-amino acid deletion variant of HGF. The variant was less abundant than the full-length transcript, but increased in parallel with native HGF mRNA in response to CCl4. The response of nonparenchymal cells to HGF was examined by plating endothelial cells and lipocytes in the presence of recombinant human HGF. Under the conditions examined, the growth factor exerted neither mitogenic nor scatter factor activity on these cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Chan A. M., Rubin J. S., Bottaro D. P., Hirschfield D. W., Chedid M., Aaronson S. A. Identification of a competitive HGF antagonist encoded by an alternative transcript. Science. 1991 Nov 29;254(5036):1382–1385. doi: 10.1126/science.1720571. [DOI] [PubMed] [Google Scholar]
  2. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  3. Friedman S. L., Roll F. J. Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal Biochem. 1987 Feb 15;161(1):207–218. doi: 10.1016/0003-2697(87)90673-7. [DOI] [PubMed] [Google Scholar]
  4. Gherardi E., Gray J., Stoker M., Perryman M., Furlong R. Purification of scatter factor, a fibroblast-derived basic protein that modulates epithelial interactions and movement. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5844–5848. doi: 10.1073/pnas.86.15.5844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gohda E., Tsubouchi H., Nakayama H., Hirono S., Sakiyama O., Takahashi K., Miyazaki H., Hashimoto S., Daikuhara Y. Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. J Clin Invest. 1988 Feb;81(2):414–419. doi: 10.1172/JCI113334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Igawa T., Kanda S., Kanetake H., Saitoh Y., Ichihara A., Tomita Y., Nakamura T. Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cells. Biochem Biophys Res Commun. 1991 Jan 31;174(2):831–838. doi: 10.1016/0006-291x(91)91493-v. [DOI] [PubMed] [Google Scholar]
  7. Irving M. G., Roll F. J., Huang S., Bissell D. M. Characterization and culture of sinusoidal endothelium from normal rat liver: lipoprotein uptake and collagen phenotype. Gastroenterology. 1984 Dec;87(6):1233–1247. [PubMed] [Google Scholar]
  8. Kan M., Zhang G. H., Zarnegar R., Michalopoulos G., Myoken Y., McKeehan W. L., Stevens J. I. Hepatocyte growth factor/hepatopoietin A stimulates the growth of rat kidney proximal tubule epithelial cells (RPTE), rat nonparenchymal liver cells, human melanoma cells, mouse keratinocytes and stimulates anchorage-independent growth of SV-40 transformed RPTE. Biochem Biophys Res Commun. 1991 Jan 15;174(1):331–337. doi: 10.1016/0006-291x(91)90524-b. [DOI] [PubMed] [Google Scholar]
  9. Kinoshita T., Tashiro K., Nakamura T. Marked increase of HGF mRNA in non-parenchymal liver cells of rats treated with hepatotoxins. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1229–1234. doi: 10.1016/0006-291x(89)92733-2. [DOI] [PubMed] [Google Scholar]
  10. Labarca C., Paigen K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem. 1980 Mar 1;102(2):344–352. doi: 10.1016/0003-2697(80)90165-7. [DOI] [PubMed] [Google Scholar]
  11. Lindroos P. M., Zarnegar R., Michalopoulos G. K. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology. 1991 Apr;13(4):743–750. [PubMed] [Google Scholar]
  12. Lindroos P. M., Zarnegar R., Michalopoulos G. K. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology. 1991 Apr;13(4):743–750. [PubMed] [Google Scholar]
  13. Lokker N. A., Mark M. R., Luis E. A., Bennett G. L., Robbins K. A., Baker J. B., Godowski P. J. Structure-function analysis of hepatocyte growth factor: identification of variants that lack mitogenic activity yet retain high affinity receptor binding. EMBO J. 1992 Jul;11(7):2503–2510. doi: 10.1002/j.1460-2075.1992.tb05315.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Maher J. J., McGuire R. F. Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo. J Clin Invest. 1990 Nov;86(5):1641–1648. doi: 10.1172/JCI114886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Masumoto A., Yamamoto N. Sequestration of a hepatocyte growth factor in extracellular matrix in normal adult rat liver. Biochem Biophys Res Commun. 1991 Jan 15;174(1):90–95. doi: 10.1016/0006-291x(91)90489-t. [DOI] [PubMed] [Google Scholar]
  16. Matsumoto K., Hashimoto K., Yoshikawa K., Nakamura T. Marked stimulation of growth and motility of human keratinocytes by hepatocyte growth factor. Exp Cell Res. 1991 Sep;196(1):114–120. doi: 10.1016/0014-4827(91)90462-4. [DOI] [PubMed] [Google Scholar]
  17. Matsumoto K., Tajima H., Hamanoue M., Kohno S., Kinoshita T., Nakamura T. Identification and characterization of "injurin," an inducer of expression of the gene for hepatocyte growth factor. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3800–3804. doi: 10.1073/pnas.89.9.3800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Matsumoto K., Tajima H., Nakamura T. Hepatocyte growth factor is a potent stimulator of human melanocyte DNA synthesis and growth. Biochem Biophys Res Commun. 1991 Apr 15;176(1):45–51. doi: 10.1016/0006-291x(91)90887-d. [DOI] [PubMed] [Google Scholar]
  19. Matsumoto K., Takehara T., Inoue H., Hagiya M., Shimizu S., Nakamura T. Deletion of kringle domains or the N-terminal hairpin structure in hepatocyte growth factor results in marked decreases in related biological activities. Biochem Biophys Res Commun. 1991 Dec 16;181(2):691–699. doi: 10.1016/0006-291x(91)91246-9. [DOI] [PubMed] [Google Scholar]
  20. Miyazawa K., Kitamura A., Naka D., Kitamura N. An alternatively processed mRNA generated from human hepatocyte growth factor gene. Eur J Biochem. 1991 Apr 10;197(1):15–22. doi: 10.1111/j.1432-1033.1991.tb15876.x. [DOI] [PubMed] [Google Scholar]
  21. Morimoto A., Okamura K., Hamanaka R., Sato Y., Shima N., Higashio K., Kuwano M. Hepatocyte growth factor modulates migration and proliferation of human microvascular endothelial cells in culture. Biochem Biophys Res Commun. 1991 Sep 16;179(2):1042–1049. doi: 10.1016/0006-291x(91)91924-2. [DOI] [PubMed] [Google Scholar]
  22. Nagaike M., Hirao S., Tajima H., Noji S., Taniguchi S., Matsumoto K., Nakamura T. Renotropic functions of hepatocyte growth factor in renal regeneration after unilateral nephrectomy. J Biol Chem. 1991 Dec 5;266(34):22781–22784. [PubMed] [Google Scholar]
  23. Nakamura T., Nawa K., Ichihara A., Kaise N., Nishino T. Purification and subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett. 1987 Nov 30;224(2):311–316. doi: 10.1016/0014-5793(87)80475-1. [DOI] [PubMed] [Google Scholar]
  24. Noji S., Tashiro K., Koyama E., Nohno T., Ohyama K., Taniguchi S., Nakamura T. Expression of hepatocyte growth factor gene in endothelial and Kupffer cells of damaged rat livers, as revealed by in situ hybridization. Biochem Biophys Res Commun. 1990 Nov 30;173(1):42–47. doi: 10.1016/s0006-291x(05)81018-6. [DOI] [PubMed] [Google Scholar]
  25. Okajima A., Miyazawa K., Kitamura N. Primary structure of rat hepatocyte growth factor and induction of its mRNA during liver regeneration following hepatic injury. Eur J Biochem. 1990 Oct 24;193(2):375–381. doi: 10.1111/j.1432-1033.1990.tb19349.x. [DOI] [PubMed] [Google Scholar]
  26. Ramadori G., Neubauer K., Odenthal M., Nakamura T., Knittel T., Schwögler S., Meyer zum Büschenfelde K. H. The gene of hepatocyte growth factor is expressed in fat-storing cells of rat liver and is downregulated during cell growth and by transforming growth factor-beta. Biochem Biophys Res Commun. 1992 Mar 16;183(2):739–742. doi: 10.1016/0006-291x(92)90545-v. [DOI] [PubMed] [Google Scholar]
  27. Rhoads D. D., Dixit A., Roufa D. J. Primary structure of human ribosomal protein S14 and the gene that encodes it. Mol Cell Biol. 1986 Aug;6(8):2774–2783. doi: 10.1128/mcb.6.8.2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Roberts A. B., McCune B. K., Sporn M. B. TGF-beta: regulation of extracellular matrix. Kidney Int. 1992 Mar;41(3):557–559. doi: 10.1038/ki.1992.81. [DOI] [PubMed] [Google Scholar]
  29. Roberts A. B., Sporn M. B. Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta. Am Rev Respir Dis. 1989 Oct;140(4):1126–1128. doi: 10.1164/ajrccm/140.4.1126. [DOI] [PubMed] [Google Scholar]
  30. Rubin J. S., Chan A. M., Bottaro D. P., Burgess W. H., Taylor W. G., Cech A. C., Hirschfield D. W., Wong J., Miki T., Finch P. W. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):415–419. doi: 10.1073/pnas.88.2.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schirmacher P., Geerts A., Pietrangelo A., Dienes H. P., Rogler C. E. Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells. Hepatology. 1992 Jan;15(1):5–11. doi: 10.1002/hep.1840150103. [DOI] [PubMed] [Google Scholar]
  32. Seki T., Ihara I., Sugimura A., Shimonishi M., Nishizawa T., Asami O., Hagiya M., Nakamura T., Shimizu S. Isolation and expression of cDNA for different forms of hepatocyte growth factor from human leukocyte. Biochem Biophys Res Commun. 1990 Oct 15;172(1):321–327. doi: 10.1016/s0006-291x(05)80212-8. [DOI] [PubMed] [Google Scholar]
  33. Strain A. J., Ismail T., Tsubouchi H., Arakaki N., Hishida T., Kitamura N., Daikuhara Y., McMaster P. Native and recombinant human hepatocyte growth factors are highly potent promoters of DNA synthesis in both human and rat hepatocytes. J Clin Invest. 1991 May;87(5):1853–1857. doi: 10.1172/JCI115207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tajima H., Higuchi O., Mizuno K., Nakamura T. Tissue distribution of hepatocyte growth factor receptor and its exclusive down-regulation in a regenerating organ after injury. J Biochem. 1992 Mar;111(3):401–406. doi: 10.1093/oxfordjournals.jbchem.a123769. [DOI] [PubMed] [Google Scholar]
  35. Tolstoshev P., Berg R. A., Rennard S. I., Bradley K. H., Trapnell B. C., Crystal R. G. Procollagen production and procollagen messenger RNA levels and activity in human lung fibroblasts during periods of rapid and stationary growth. J Biol Chem. 1981 Mar 25;256(6):3135–3140. [PubMed] [Google Scholar]
  36. Weidner K. M., Arakaki N., Hartmann G., Vandekerckhove J., Weingart S., Rieder H., Fonatsch C., Tsubouchi H., Hishida T., Daikuhara Y. Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7001–7005. doi: 10.1073/pnas.88.16.7001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Weidner K. M., Behrens J., Vandekerckhove J., Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol. 1990 Nov;111(5 Pt 1):2097–2108. doi: 10.1083/jcb.111.5.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yanagita K., Nagaike M., Ishibashi H., Niho Y., Matsumoto K., Nakamura T. Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs. Biochem Biophys Res Commun. 1992 Jan 31;182(2):802–809. doi: 10.1016/0006-291x(92)91803-x. [DOI] [PubMed] [Google Scholar]
  39. Zarnegar R., DeFrances M. C., Kost D. P., Lindroos P., Michalopoulos G. K. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem Biophys Res Commun. 1991 May 31;177(1):559–565. doi: 10.1016/0006-291x(91)92020-k. [DOI] [PubMed] [Google Scholar]
  40. Zarnegar R., Michalopoulos G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 1989 Jun 15;49(12):3314–3320. [PubMed] [Google Scholar]

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