Download PDF
Horm Metab Res 2001; 33(7): 394-401
DOI: 10.1055/s-2001-16229
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Expression and Distribution of the Prolactin Receptor in Normal Rat Liver and in Experimental Liver Cirrhosis

S. Kloehn 1 , C. Otte 1 , M. Korsanke 1 , T. Arendt 1 , A. Clemens 2 , A. Glasow 3 , S. R. Bornstein 4 , U. R. Fölsch 1 , H. Mönig 1
  • 1 Department of Medicine, University of Kiel, Germany
  • 2 Department of Pathology, University of Kiel, Germany
  • 3 Department of Internal Medicine III, University of Leipzig, Germany
  • 4 National Institute of Child Health and Human Development, Bethesda, Maryland
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Also available at
    Permissions and Reprints

Recent results have suggested a role for prolactin (PRL) as a regeneration factor in the liver. In order to investigate the involvement of prolactin in the pathogenesis of liver cirrhosis, we studied the expression of the prolactin receptor (PRLR) and PRL during the development of cirrhosis in an animal model. 30 male rats were exposed to CCl4 by inhalation. Phenobarbitone was added to the drinking water to accelerate the formation of toxic metabolites by enzyme induction. Two control groups of 30 animals each were treated with phenobarbitone only or received no treatment. 10 animals of each group were sacrificed 35, 55, and 70 days after initiation of treatment. Liver tissue was subjected to histological examination, which demonstrated fibrosis of different grades and cirrhosis in the CCl4-treated rats. Expression of PRLR mRNA was investigated by mRNA extraction, RT-PCR and computer-supported densitometric evaluation. Compared to control liver, PRLR mRNA was expressed at a higher level in fibrotic and cirrhotic liver specimens. In normal tissue, immunohistochemical staining showed a high concentration of PRLR around the central vein and in the epithelium of the bile ducts. This pattern of distribution was lost in fibrosis and cirrhosis. An accumulation of PRLR was demonstrated within the damaged cells. Neither PRL nor PRL mRNA was detectable in normal, fibrotic, or cirrhotic liver. We conclude that PRLR is distributed in normal rat liver in a typical pattern which is lost with increasing fibrosis. PRL is not produced by rat liver, indicating that PRL does not act through autocrine or paracrine mechanisms.

Key words:

Prolactin - Fibrogenesis - Regeneration Factor - Metabolic Zoning

References

  • 1 Ben-Jonathan N, Mershon J L, Allen D J, Steinmetz R W. Extrapituitary prolactin: distribution, regulation, functions and clinical aspects.  Endocr Rev. 1996;  17 639-669
    CrossrefPubMedGoogle Scholar
  • 2 Nagano M, Kelly P A. Tissue distribution and regulation of rat prolactin receptor gene expression.  J Biol Chem. 1994;  269 13 337-13 345
    PubMedGoogle Scholar
  • 3 Boutin J M, Joliceur, Okamura H, Gagnon J, Edery M, Shirota M C, Banville D, Dusanter-Fourt I, Djiane J, Kelly P A. Cloning and expression of the rat prolactin receptor, a member of the growth hormone/prolactin receptor gene family.  Cell. 1990;  53 69-77
    PubMedGoogle Scholar
  • 4 Shirota M C, Banville D, Ali S, Joliceur S, Boutin J M, Edery M, Djiane J, Kelly P A. Expression of two forms of prolactin receptor in rat ovary and liver.  Mol Endocrinol. 1990;  124 1136-1143
    PubMedGoogle Scholar
  • 5 Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly P A. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice.  Endocr Rev. 1998;  19 225-268
    CrossrefPubMedGoogle Scholar
  • 6 Maetz J. Mechanisms of salt and water transfer across membranes in teleosts in relation to the aquatic environment.  Mem Soc Endocrinol. 1970;  18 3-29
    PubMedGoogle Scholar
  • 7 Hirano T, Johnson D W, Bern H A. Control of water movement in flounder urinary bladder by prolactin.  Nature. 1971;  230 469-470
    PubMedGoogle Scholar
  • 8 Richardson B P. Evidence for a physiologic role of prolactin in osmoregulation in the rat after its inhibition by 2-bromo-α-ergokryptine.  Br J Pharmacolol. 1973;  47 623P-624P
    PubMedGoogle Scholar
  • 9 Robertson M T, Boyajian M J, Patterson K, Robertson W V. Modulation of the chlorid concentration of human sweat by prolactin.  Endocrinology. 1986;  119 2439-2444
    CrossrefPubMedGoogle Scholar
  • 10 Blüm V, Fiedler K. Hormonal control of reproductive behavior in some cichlid fish.  Gen Comp Endocrinol. 1965;  5 186-196
    CrossrefPubMedGoogle Scholar
  • 11 Janik D S, Buntin J D. Behavioral and physiological effects of prolactin in incubating ring doves.  J Endocrinol. 1985;  105 201-209
    PubMedGoogle Scholar
  • 12 Bridges R S, Robertson M C, Shiu R P, Sturgis J D, Henriquez B M, Mann P E. Central lactogenic regulation of maternal behavior in rats: steroid dependence, hormone specificity, and behaviroral potencies of rat prolactin and rat placental lactogen I.  Endocrinology. 1997;  138 756-763
    CrossrefPubMedGoogle Scholar
  • 13 Noel M B, Woodsite B. Effects of systemic and central prolactin injections of food intake, weight gain, and estrus cyclicity in females rats.  Physiol Behav. 1993;  54 151-154
    CrossrefPubMedGoogle Scholar
  • 14 Ramaswamy S, Viswanathan S, Bapna J S. Effect of prolactin on tolerance and dependence to acute administration of morphine.  Neuropharmacology. 1987;  26 111-113
    CrossrefPubMedGoogle Scholar
  • 15 Ramaswamy S, Suthakaran C, Bapna J S. Role of GABAergic system in prolactin analgesia.  Clin Exp Pharmacol Physiol. 1989;  16 893-896
    PubMedGoogle Scholar
  • 16 Ramaswamy S, Regunathan S, Bapna J S. Anticholinesterase activity of prolactin: correlation with analgesia.  J Pharm Pharmacol. 1988;  40 306-307
    PubMedGoogle Scholar
  • 17 Bernton E W, Meltzer M S, Holaday J W. Suppression of macrophage activation and T-lymphocyte function in hypoprolactinemic mice.  Science. 1988;  239 401-404
    PubMedGoogle Scholar
  • 18 Berczi I, Nagy, Kovacs K, Horvath E. Regulation of humoral immunity in rats by pituitary hormones.  Acta Endocrinol (Copenh). 1981;  98 506-513
    PubMedGoogle Scholar
  • 19 Nagy E, Berczi I. Prolactin and contact sensitivity.  Allergy. 1981;  36 429-431
    PubMedGoogle Scholar
  • 20 Sabharwal P, Gaser R, LaFuse W, Varma S, Liu Q, Arkins S, Kooijman R, Kutz L, Kelly K W, Malarkey W E. Prolactin synthesized and secreted by human peripheral blood mononuclear cells: an autocrine growth factor for lymphoproliferation.  Proc Natl Acad Sci USA. 1992;  89 7713-7716
    PubMedGoogle Scholar
  • 21 Machida T, Taga M, Minaguchi H. Effect of prolactin on lipoprotein lipase activity in the rat fetal liver. Asia. Oceania.  J Obstet Gynaecol. 1990;  16 261-265
    PubMedGoogle Scholar
  • 22 Villalba M, Zabala M T, Martinez-Serrano A, de la Colina R, Satrustegui J, Garcia-Ruiz J P. Prolactin increases cytosolic free calcium concentration in hepatocytes of lactating rats.  Endocrinology. 1991;  129 2857-2861
    PubMedGoogle Scholar
  • 23 Sorenson R L, Brelje T C, Hegre O D, Marshall S, Anaya P, Sheridan J D. Prolactin (in vitro) decreases the glucose stimulation threshold, enhances insulin concentration, and increases dye coupling among islet β cells.  Endocrinology. 1987;  121 1447-1453
    PubMedGoogle Scholar
  • 24 Glasow A, Breidert M, Haidan A, Anderegg U, Kelly P A, Bornstein S. Functional aspects of the effect of prolactin (PRL) on adrenal steroidogenesis and distribution of PRL receptor in the human adrenal gland.  J Clin Endocinol Metab. 1996;  81 3103-3111
    CrossrefPubMedGoogle Scholar
  • 25 Vergani G, Mayerhofer A, Bartke A. Acute effects of rat growth hormon (GH), human GH, and prolactin on proliferating rat liver cells in vitro: a study of mitotic behavior and ultrastructural alterations.  Tissue Cell. 1994;  26 457-465
    CrossrefPubMedGoogle Scholar
  • 26 Richards J F. Ornithin decarboxylase activity in tissues of prolactin-treated rats.  Biochem Biophys Res Commun. 1975;  63 292-299
    CrossrefPubMedGoogle Scholar
  • 27 Crowe P D, Buckley A R, Zorn N E, Rui H. Prolactin activates protein kinase C and stimulates growth-related gene expression in rat liver.  Mol Cell Endocrinol. 1991;  79 29-35
    CrossrefPubMedGoogle Scholar
  • 28 Hill D J, Francis M J, Miner R D. Action of rat prolactin on plasma somatomedin levels in the rat and on somatomedin release from perfused rat liver.  J Endocrinol. 1977;  75 137-143
    PubMedGoogle Scholar
  • 29 Berlanga J J, Varat J AF, Martin-Perez J, Garcia-Ruiz, JP. Prolactin receptor is associated with c-src kinase in rat liver.  Mol Endocrinol. 1995;  9 1461-1467
    CrossrefPubMedGoogle Scholar
  • 30 Buckley A R. Prolactin administration stimulates rat hepatic DNA synthesis. Biochem Biophys Res.  Commun. 1986;  138 1138-1145
    PubMedGoogle Scholar
  • 31 Takamori S, Bakshi M, Kothary H, Shiota K, Walker A M. Intrahepatic prolactin following partial hepatectomy.  Washington:; 77th Annual Meeting of the Endocrine Society. Abstract Book, 1995 296
    Google Scholar
  • 32 Fausto N, Mead J E. Regulation of liver growth: Protooncogenes and transforming growth factors.  Hepatology. 1989;  60 4-13
    PubMedGoogle Scholar
  • 33 Meyer-Alber A, Hartmann H, Stümpel F, Creutzfeldt W. Mechanism of insulin resistance in CCl4-induced cirrhosis of rats.  Gastroenterology. 1992;  102 223-229
    PubMedGoogle Scholar
  • 34 Batts KP and Ludwig J. Chronic hepatitis. An update on terminology and reporting.  Am J Surg Pathol. 1995;  19 1409-1417
    CrossrefPubMedGoogle Scholar
  • 35 Buckley A R, Crowe P D, Russell D H. Rapid activation of a protein kinase C in isolated rat liver nuclei by prolactin, a known hepatic mitogen.  Proc Natl Acad Sci USA. 1988;  85 8649-8653
    PubMedGoogle Scholar
  • 36 Picoletti R, Maroni P, Bendinelli P, Bernelli-Zazzera A. Rapid stimulation of mitogen-activated protein kinase of rat liver by prolactin.  Biochem J. 1994;  303 429-433
    PubMedGoogle Scholar
  • 37 Santi P, Martelli A M, Gilmour R S, Falcieri E, Rana R, Cataldi A, Lattenzi G, Bareggi R, Coco L. Changes in phosphoinositide level in rat liver nuclei in response to prolactin, a known hepatic mitogen.  Cell Signal. 1992;  4 385-391
    CrossrefPubMedGoogle Scholar
  • 38 Hurley T W, Kuhn C M, Schonberg S M, Handwerger S. Differential effects of placental lactogen, growth hormone and prolactin on rat liver ornithin decarboxylase activity in the perinatal period.  Life Sci. 1980;  27 2269-2275
    CrossrefPubMedGoogle Scholar
  • 39 Haber B A, Mohn K L, Diamond R, Taub R. Inductionspattern of 70 genes during nine days after hepatectomy define the temporal course of liver regeneration. J Clin.  Invest. 1993;  91 1319-1326
    PubMedGoogle Scholar
  • 40 Buckley A R, Crowe P D, Bauman P A, Neumayer L A, Larid H E 2nd, Russell D H, Putnam C W. Prolactin-provoked alterations of cytosolic membrane and nuclear protein kinase C following partial hepatectomy. Dig Dis.  Sci. 1991;  36 1313-1319
    PubMedGoogle Scholar
  • 41 Gala R R, Shevach E M. Evidence for the release of a prolactin-like substance by mouse lymphocytes and macrophages.  Proc Soc Exp Biol Med. 1994;  205 12-19
    PubMedGoogle Scholar
  • 42 Zhu X H, Zellweger R, Ayala A, Chaudry I CH. Prolactin inhibits the increased cytokine gene expression in Kupffer cells following acute hemorrhage.  Cytokine. 1996;  8 134-146
    CrossrefPubMedGoogle Scholar
  • 43 Tomiya T, Tani M, Yamada S, Hayashi S, Umeda N, Fujiwara S. Serum hepatocyte growth factor levels in hepatectomized and non-hepatectomized surgical patients.  Gastroenterology. 1992;  193 1621-1624
    PubMedGoogle Scholar
  • 44 Shiota G, Wang T C, Nakamura T, Schmidt E V. Hepatocyte growth factor in transgenic mice: effects on hepatocyte growth, liver regeneration and gene expression.  Hepatology. 1994;  19 962-972
    CrossrefPubMedGoogle Scholar
  • 45 Wiedemann E, Schwartz E, Frantz A G. Acute and chronic estrogen effects upon serum somatomedine activity, growth hormone and prolactin in men.  J Clin Endocrinol Metab. 1976;  42 942-952
    PubMedGoogle Scholar
  • 46 Goffin V, Kelly P A. Prolactin and growth hormone receptors.  Clin Endocrinol. 1996;  45 247-255
    CrossrefPubMedGoogle Scholar
  • 47 Cunningham B C, Bass S, Fuh G, Wells J A. Zinc mediation of the binding of human growth hormone to the human prolactin receptor.  Science. 1990;  250 1709-1712
    PubMedGoogle Scholar
  • 48 Jungermann K, Katz N. Functional hepatocellular heterogeneity.  Hepatology. 1982;  2 385
    PubMedGoogle Scholar
  • 49 Jungermann K, Katz N. Functional specialisation of different hepatocyte population.  Physiol Rev. 1989;  69 708-764
    PubMedGoogle Scholar
  • 50 Kumari T M, Govindarajulu P. Hyperglycemic effect of prolactin in anterior pituitary transplanted rats.  Endocrinol Jpn. 1990;  37 819-825
    PubMedGoogle Scholar
  • 51 Luquita M G, Catania V A, Sanchez-Pozzi E J, Mottino A D. Ovine prolactin increases hepatic UDP-glucuronosyltransferase activity in ovariectomized rats.  J Pharmacol Exp Ther. 1996;  278 921-925
    PubMedGoogle Scholar
  • 52 Smirnova O V, Petrascuk O M, Kelly P A. Immunocytochemical localization of prolactin receptors in rat liver cells: I. Dependence on sex and sex steroids.  Mol Cell Endocrinol. 1994;  105 77-81
    CrossrefPubMedGoogle Scholar
  • 53 Liu Y, Ganguly T, Hyde J F, Vore M. Prolactin increases mRNA encoding Na+-TC co-transport polypeptide and hepatic Na+-TC co-transport.  Am J Physiol. 1995;  268 11-17
    PubMedGoogle Scholar
  • 54 Liu Y, Suchy F J, Silvermann J A, Vore M. Prolactin increases ATP-dependent taurocholate transport in canalicular plasma membrane from rat liver.  Am J Pysiol. 1997;  272 G46-G53
    PubMedGoogle Scholar

Sievert Kloehn,M.D. 

1. Med. Klinik der CAU Kiel

Schittenhelmstrasse 12
24105 Kiel
Germany


Phone: + 49 (431) 597 1393

Fax: + 49 (431) 597 1302

Email: skloehn@1med.uni-kiel.de