SVIBOR - Project code: 3-01-253

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Project code: 3-01-253


MOLECULAR PATHOBIOCHEMISTRY OF LIVER CELL PROLIFERATION


Main researcher: TOPIĆ, ELIZABETA (50266)


Assistants
Type of research: basic
Duration from: 03/29/91. to 12/31/95.
Papers on project (total): 34
Papers on project quoted in Current Contents: 4
Institution name: KBC, Znanstvena jedinica za patobiokemijska i klinička istraživanja, Zagreb (167)
Department/Institute: Clinical Institute of Chenistry Zagreb University school of Mede Department of Experimental medicine, Rudjer Bošković Institute Department of Gastroenterology, Ineternal Clinic Sestre Milosrde
Address: Vinogradska 29
City: 10000 - Zagreb, Croatia
Communication
Phone: 385-1-572-730
Fax: 385-1-572-730
Summary: A liver specific but species nonspecific growth factor named hepatopoietin, first descriebed in 1978, is an acid- and heat-stable glycoprotein, MW 38.000+5.000 D found in the liver extract isolated from liver remnant 17 and 50 hours after partial hepatectomy. The studies performed so far have shown that hepatopoietin extract (rLHP) induces hepatocyte proliferation in vivo, in rats and in vitro in hepatocyte primary culture. Measured by flow cytometer it was recognized that hepatopoetin extract acts in the S phase of the cell cycle. Magnesium, Galctose and Trypsin decrease its action. Sodium- dodecyl-sulphatpolyacrylamide electrophoresis (SDS-PAGE) showed that rLHP extract separated into at least three fractions between 30000 and 45000 D; hepatopoietin band at 33800 D, at 38000 D and at 41700 D, according to the low molecular weight marker. By the further purification by chromatography, the biological activity of hepatopoietin extract was something higher (i.e. 2.5 to 3.0 times). An extract inducing hepatocyte proliferation in primary culture, and characterized by almost identical physico-chemical properties and biologic activity as that isolated from rat liver remnants, has also been isolated from plasma of liver disease patients. Furthermore, comparison of the way of action of human serum and rat liver hepatopoietin extract as measured by flowcytometry, has revealed the content of cell DNA in the S phase of the cell cycle to be increased, suggesting the human plasma extract of liver disease patients to stimulate the hepatocyte DNA synthesis similarly but somewhat more affectively than the rat liver extract. These results appears to be the first results on hepatopoietin obtained in humans. The results on proliferative activity of hPHP extract isolated from liver disease patients was the highest in chronic liver disease patients (mean, 96% above the control), then in primary (mean, 69%), and secondary (mean, 49%) carcinoma. The smallest proliferative activity was observed in cirrhosis patients. The SDS-PAGE hepatopoietin protein bands was evaluated with biochemical markers of liver impairement. Further studies on the role of hepatopoietin in pathobiochemistry of liver proliferation at the biochemical and gene level have just been in the course.

Keywords: Hepatopoietin, liver specific growth factor, hepatocyte proliferation, primary hepatocyte culture, proliferative activity

Research goals: Knowledge about the nature and function of newly discovered growth factors as the key molecules in the control of cellular growth, one of them hepatopoietin, provides additional information on the pathogenesis of hepatocyte proliferation. The aims of this investigation are: 1) to determine the structure and function of hepatopoietin, 2) to study the genetic and biochemical mechanisms of effect of hepatopoietin on hepatocyte proliferation using methods of analytical biochemistry and DNA technology thereby, and 3) to evaluate the use of hepatopoietinin early detection of malignant proliferation or tissue regeneration in clinical material. In the view of the frequency of liver disease both in our population and worldwide, the importance of investigation of the molecular pathobiochemistry of hepatocyte proliferation surelly justify the above aims. Recognition of growth factors as a their genes and specific genes controlling the growth factors appears to be an unavoidable precondition for complete grasping of the molecular mechanism of oncogenesis, which will be of utmost importance in planning future treatment of the disease. The treatment shoud be directed towards blocking of the products of these genes, resulting in interruption of the course of proliferation. As the period of intense and systematic research in the field of oncogenes and oncogene products in particular types of tumors has already begun both in Croatia and worldwidw, we believe that further studies of growth factors are fully justified and have their full place and purpose.

COOPERATION - INSTITUTIONS


  1. Name of institution: Department of Experimental Medicine, Max Planck Institute of Biochemistry
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: D-82152 - Martinsried by Munich, Germany

  2. Name of institution: Odjel za eksperimentalnu medicinu Institut Ruđer Bošković
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 10000 - Zagreb, Croatia

  3. Name of institution: Odjel za molekularnu medicinu Institut Ruđer Bošković
    Type of institution: University/Faculty
    Type of cooperation: Systematic exchange of information
    City: 10000 - Zagreb, Croatia

  4. Name of institution: Klini;ki zavod za laboratorijsku dijagnostiku KBC-Zagreb
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 10000 - Zagreb, Croatia

  5. Name of institution: Zavod za medicinsku biokemiju Farmaceustko biokemijskog fakulteta Sveu;iliŠta u Zagrebu
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 10000 - Zagreb, Croatia

  6. Name of institution: Zavod za kemiju i biokemiju Medicinskog fakulteta Sveu;iliŠta u Zagrebu
    Type of institution: University/Faculty
    Type of cooperation: Occasional exchange of information
    City: 10000 - Zagreb, Croatia

OTHER ACHIEVEMENTS


  1. Name: Pročišćeni ekstrakt hepatopoietina
    Type of achievement: Studies of conduct
    Authors: Topić E., Zadro R., Gluhak J., Slijepčević M., Ruhenstroth-Bauer G., Vogl S., Hoffmann G.
Other information about the project.
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