Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Abstract

mones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP3 levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. (8), prolactin (58), and progesterone (25). The cAMP/ERK1/2/Elk-1 signaling has been shown to play a key role in the regulation of cholangiocyte proliferation (18,20,24,27,37). For example, whereas increased cAMP levels sustain cholangiocyte growth (20,24,27,37), decreased cAMP synthesis results in inhibition of cholangiocyte hyperplasia (24,27,37).Follicle-stimulating hormone (FSH) is the central hormone of the mammalian reproduction (55). FSH, also called gonadotropin because it stimulates the gonads, is produced from the anterior pituitary gland of the brain (60). FSH is a large glycoprotein composed of alpha and beta subunits, similar to those of luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG) (1). The alpha subunits of FSH, LH, TSH, and hCG are identical, whereas the beta subunit is unique and endows each hormone with the ability to binds to its own receptor (60). FSH interacts with a receptor protein that has seven transmembrane-spanning domains; its binding is transduced into an intracellular signal via the heterotrimeric G proteins (61). Following coupling of the FSHR to G␣ s adenylyl cyclase is stimulated, followed by production of cAMP and activation of PKA, which phosphorylates structural proteins, enzymes, and transcriptional activators (32,66). Whether the FSH receptor is also linked to G␣ i has not yet been completely defined. In fact, the treatment of Sertoli cells with pertussis toxin (PTX, a G␣ i inhib...

Castration inhibits biliary proliferation induced by bile duct obstruction: novel role for the autocrine trophic effect of testosterone

“…In response to bile duct ligation (BDL), there is enhanced biliary hyperplasia and secretin-stimulated choleresis (a functional marker of cholangiocyte growth) (2,3,18,22), whereas, following the administration of hepatotoxins (e.g., carbon tetrachloride), there is loss of cholangiocyte mass and secretory function (36). Indeed, proliferating cholangiocytes serve as neuroendocrine cells secreting and responding to a number of hormones and neuropeptides contributing to the autocrine and paracrine pathways that modulate the homeostasis of the biliary epithelium (8,16,18,19,22,23,39).…”

“…Cholangiocyte growth/apoptosis is regulated by a number of factors, including gastrointestinal hormones, the second messenger system, cAMP, and sex hormones, including estrogens, prolactin, follicle-stimulating hormone, and progesterone (7,8,17,23,39,49). Regarding sex hormones, estrogens have been shown to sustain cholangiocyte proliferation and reduce cholangiocyte apoptosis (6,7).…”

“…Progesterone enhances the proliferative activity of female and male cholangiocytes via autocrine mechanisms, since cholangiocytes possess the enzymatic pathway for steroidogenesis (23). Folliclestimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1 (39).…”

The Rats Liver External Secretory Function in Blockade of Androgen Receptors With Flutamide

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