Prolactin's role in the early stages of liver regeneration in rats

Abstract

Liver regeneration after partial hepatectomy (PHx) is a complex process that is regulated by hemodynamic changes, the modulation of cytokines and growth factors, and the activation of immediate early transcription factors that lead to a round of hepatocyte mitosis. Among the factors involved, the pituitary hormone prolactin (PRL) has been shown to induce a hepatotrophic response after partial hepatectomy similar to that caused by phorbol esters; and in isolated hepatocytes PRL triggers a mitogenic response. However, it is becoming clear that PRL exerts a dual role acting in proliferation and differentiation processes. In this work, we have assessed the role of PRL in the early stages of liver regeneration in rats. To this end, three groups of rats were compared: Sham operated, regenerant and regenerant with PRL i.p. administration. Results show that PRL administration prior to partial hepatectomy caused an increase in the binding activity of several transcription factors involved in cell proliferation: AP-1, c-Jun and STAT-3, and in liver-specific differentiation and maintenance of energetic metabolism: CEBPalpha, HNF-1, HNF-4 at early time points and at later time points HNF-3. Hepatic sections show that PRL administration increases the number of proliferating cells within 5 h post-partial hepatectomy. The mRNA of the angiogenic and survival factors VEGF and HIF-1alpha, was also induced by PRL treatment. Data indicate that PRL triggers, either directly or indirectly, an acceleration of liver regeneration, preserving liver function and fulfilling a hepatoprotective role. J. Cell. Physiol. 219: 626-633, 2009. (c) 2009 Wiley-Liss, Inc.

Regulation of Blood Vessels by Prolactin and Vasoinhibins

“…PRL stimulates angiogenesis during development (chick chorioallantoic membrane, CAM) and in adult tissues (corpus luteum, testis, and heart). These observations were recently extended to include the angiogenesis of transplanted pancreatic islets [37] and the neovascularization associated with normal and regenerative liver growth, where inducing hyperprolactinemia increased hepatic endothelial cell proliferation and vascular endothelial growth factor (VEGF) expression [38,39]. Moreover, in addition to the known effects of PRL on endothelial cell proliferation and VEGF expression, PRL was recently shown to stimulate the migration and tube formation of endothelial cells [40,41], to reduce vasopermeability by upregulating the expression of tight-junction proteins between endothelial cells [42], and to promote intussusceptive angiogenesis in the CAM [40].…”

Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis

“…PRL also influences early events of liver regeneration leading to animal survival and hepatic growth. Circulating PRL levels increase shortly after PH (9), and PRL administration stimulates the binding activity of AP-1, JUN, and STAT-3 within the first 5 to 12 h following PH (36). Activation of these transcriptional factors is part of the signaling cascade elicited by important cytokines, including IL-6, to promote hepatoprotection and mitogenesis (14,43).…”

“…PRL triggers mitogenic signaling pathways in isolated hepatocytes (4) and may also promote liver growth by inducing angiogenesis. PRL stimulates endothelial cell proliferation in various organs through direct stimulation of endothelial cells (13) but also indirectly by inducing the synthesis of VEGF and fibroblast growth factor-2 in nonendothelial cells (13), and it promotes VEGF expression in regenerating livers (36).…”

“…Its levels are high in neonates (21), in pregnant and lactating females (3), in patients with liver cirrhosis (33), and in rodents after partial hepatectomy (PH) (9). Liver is the organ that expresses the highest levels of PRL receptors (34), and injection of PRL increases hepatic DNA synthesis, the liver-to-body weight ratio (LBW) (10), and activity of transcription factors involved in hepatic cell proliferation [activator protein-1 (AP-1), Jun, STAT-3] (36). PRL triggers mitogenic signaling pathways in isolated hepatocytes (4) and may also promote liver growth by inducing angiogenesis.…”

Use of Prolactin Receptor Antagonist to Better Understand Prolactin Regulation of Pituitary Homeostasis

“…Prolactin stimulates proliferation of mammary gland epithelium [43], hepatocytes [44], pancreatic beta cells [45], prostate epithelial cells [23], astrocytes [46], neurons [25] and various cells of the immune system [47]. Many of these actions are associated with adaptation to litter care, e.g.…”