Expression and Distribution of Prolactin Receptor in Normal, Fibrotic, and Cirrhotic Human Liver

Abstract

Liver cirrhosis is often associated with elevated levels of prolactin (PRL). This is commonly attributed to impaired hepatic metabolism of estrogens. However, there is evidence suggesting that PRL may be an important factor in hepatic tissue regeneration. To investigate the role of PRL in the pathogenesis of liver cirrhosis, we used RT-PCR and immunhistochemical staining to analyze changes in the expression and the histological distribution of the prolactin receptor (PRLR) in normal, fibrotic and cirrhotic hepatic tissue. Liver tissue was obtained from 29 surgically explanted human livers. The histological examination demonstrated normal liver tissue (n=9) as well as different grades of fibrosis (n=10) and cirrhosis (n=10). In liver cirrhosis and fibrosis, PRLR-mRNA was expressed at a higher level compared to normal liver specimens. Immunohistochemical staining of normal liver tissue demonstrated homogeneous distribution of the PRLR in the hepatocytes and in the epithelial cells of the bile ducts. This pattern of distribution was lost in fibrosis, where an accumulation of the PRLR was observed in the damaged hepatocytes. As no PRL-mRNA was detectable in normal, fibrotic or cirrhotic tissue, PRL does not act through autocrine or paracrine mechanisms. These data confirm previous results, which we obtained using an animal model for experimental liver cirrhosis in rats suggesting a metabolic function of PRL in normal liver and a regenerative function in fibrotic and cirrhotic liver. In conclusion, PRL might be involved in the pathogenesis of liver cirrhosis.

Key words

Hyperprolactinemia - fibrogenesis - regeneration factor - cirrhosis

References

• 1 Banerjee R, Ginsburg E, Vonderhaar BK. Characterization of a monoclonal antibody against human prolactin receptors.  Int J Cancer. 1993;  55 712-721
• 2 Berlanga JJ, Fresno Vara JA, Martin-Pérez J, Garcia-Ruiz JP. Prolactin receptor is associated with c-src kinase in rat liver.  Mol Endocrinol. 1995;  9 1461-1467
• 3 Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice.  Endocr Rev. 1998;  19 225-268
• 4 Buckley AR, Crowe PD, Bauman PA, Neumayer LA, Laird HE, Russell DH, Putnam CW. Prolactin-provoked alterations of cytosolic, membrane, and nuclear protein kinase C following partial hepatectomy.  Dig Dis Sci. 1991;  36 1313-1319
• 5 Buckley AR, Putnam CW, Russell DH. Prolactin is a tumor promoter in rat liver.  Life Sci. 1985;  37 2569-2575
• 6 Buckley AR. Prolactin administration stimulates rat hepatic DNA synthesis.  Biochem Biophys Res Commun. 1986;  138 1138-1145
• 7 Campbell GS, Argetsinger LS, Ihle JN, Kelly PA, Rillema JA, Carter-Su C. Activation of JAK2 tyrosine kinase by prolactin receptors in Nb2 cells and mouse mammary gland explants.  Proc Natl Acad Sci USA. 1994;  91 5232-5236
• 8 Corenblum B, Shaffer EA. Hyperprolactinemia in hepatic encephalopathy may result from impaired central dopaminergic neurotransmission.  Horm Metab Res. 1989;  21 675-677
• 9 Crowe PD, Buckley AR, Zorn NE, Rui H. Prolactin activates protein kinase C and stimulates growth-related gene expression in rat liver.  Mol Cell Endocrinol. 1991;  79 29-35
• 10 Fausto N, Mead JE. Regulation of liver growth: protooncogenes and transforming growth factors.  Lab Invest. 1989;  60 4-13
• 11 Fausto N. Liver regeneration.  J Hepatol. 2000;  32 19-31
• 12 Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion.  Physiol Rev. 2000;  80 1523-1631
• 13 Garcia-Caballero T, Morel G, Gallego R, Fraga M, Pintos E, Gago D, Vonderhaar BK. et al . Cellular distribution of prolactin receptors in human digestive tissues.  J Clin Endocrinol Metab. 1996;  81 1861-1866
• 14 Goffin V, Kelly PA. The prolactin/growth hormone receptor family: structure/function relationships.  J Mammary Gland Biol Neoplasia. 1997;  2 7-17
• 15 Gressner AM, Lahme B, Brenzel A. Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells.  Hepatology. 1995;  22 1507-1518
• 16 Hill DJ, Francis MJ, Milner RD. 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
• 17 Kline JB, Roehrs H, Clevenger CV. Functional characterization of the intermediate isoform of the human prolactin receptor.  J Biol Chem. 1999;  274 35461-35468
• 18 Kloehn S, Otte C, Korsanke M, Arendt T, Clemens A, Glasow A, Bornstein SR. et al . Expression and distribution of the prolactin receptor in normal rat liver and in experimental liver cirrhosis.  Horm Metab Res. 2001;  33 394-401
• 19 Liu Y, Ganguly T, Hyde JF, Vore M. Prolactin increases mRNA encoding Na⁺-TC cotransport polypeptide and hepatic Na⁺-TC cotransport.  Am J Physiol. 1995;  268 11-17
• 20 Liu Y, Suchy FJ, Silverman JA, Vore M. Prolactin increases ATP-dependent taurocholate transport in canalicular plasma membrane from rat liver.  Am J Physiol. 1997;  272 46-53
• 21 Morgan MY, Jakobovits AW, Gore MB, Wills MR, Sherlock S. Serum prolactin in liver disease and its relationship to gynaecomastia.  Gut. 1978;  19 170-174
• 22 Mukherjee S, Kar M, Dutta S. Observation on serum prolactin in hepatic cirrhosis.  J Indian Med Assoc. 1991;  89 307-308
• 23 Nagano M, Kelly PA. Tissue distribution and regulation of rat prolactin receptor gene expression. Quantitative analysis by polymerase chain reaction.  J Biol Chem. 1994;  269 13337-13345
• 24 Nevalainen MT, Valve EM, Ingleton PM, Nurmi M, Martikainen PM, Härkönen PL. Prolactin and prolactin receptors are expressed and functioning in human prostate.  J Clin Invest. 1997;  99 618-627
• 25 Panerai AE, Salerno F, Manneschi M, Cocchi D, Müller EE. Growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with severe liver disease.  J Clin Endocrinol Metab. 1977;  45 134-140
• 26 Piccoletti R, Bendinelli P, Maroni P. Signal transduction pathway of prolactin in rat liver.  Mol Cell Endocrinol. 1997;  135 169-177
• 27 Richards JF. Ornithine decarboxylase activity in tissues of prolactin-treated rats.  Biochem Biophys Res Commun. 1975;  63 292-299
• 28 Russell DH, Larson DF, Cardon SB, Copeland JG. Cyclosporine inhibits prolactin induction of ornithine decarboxylase in rat tissues.  Mol Cell Endocrinol. 1984;  35 159-166
• 29 Thomson MJ, Richards JF. Ornithine decarboxylase and thymidine kinase activity in tissues of prolactin-treated rats: effect of hypophysectomy.  Life Sci. 1978;  22 337-344
• 30 Vergani G, Mayerhofer A, Bartke A. Acute effects of rat growth hormone (GH), human GH and prolactin on proliferating rat liver cells in vitro: a study of mitotic behaviour and ultrastructural alterations.  Tissue Cell. 1994;  26 457-465
• 31 Wernze H, Schmitz E. Plasma prolactin and prolactin release in liver cirrhosis.  Acta Hepatogastroenterol (Stuttg). 1977;  24 97-101
• 32 Yen SS, Ehara Y, Siler TM. Augmentation of prolactin secretion by estrogen in hypogonadal women.  J Clin Invest. 1974;  53 652-655

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