The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine

Abstract

The nuclear receptor liver receptor homologue-1 (LRH-1, NR5A2) is a crucial transcriptional regulator of many metabolic pathways. In addition, LRH-1 is expressed in intestinal crypt cells where it regulates the epithelial cell renewal and contributes to tumorigenesis through the induction of cell cycle proteins. We have recently identified the intestinal epithelium as an important extra-adrenal source of immunoregulatory glucocorticoids. We show here that LRH-1 promotes the expression of the steroidogenic enzymes and the synthesis of corticosterone in murine intestinal epithelial cells in vitro. Interestingly, LRH-1 is also essential for intestinal glucocorticoid synthesis in vivo, as LRH-1 haplo-insufficiency strongly reduces the intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress. These results demonstrate for the first time a novel role for LRH-1 in the regulation of intestinal glucocorticoid synthesis and propose LRH-1 as an important regulator of intestinal tissue integrity and immune homeostasis.

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

“…Initially, it was found that the thymic epithelium can synthesize GCs in a paracrine manner, and more recently, intestinal mucosa and skin have been proposed to synthesize GCs (55)(56)(57). Although very little is known about steroidogenesis in non-adrenal tissues, the concept of skin as endocrine organ is well established; it produces other hormones such as estrogen, progesterone, retinoids, and vitamin D, all of which have significant impact on its physiology and pathology (20, 58 -62).…”

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

“…This protein modulates the inflammatory responses during carcinogenesis, and its overexpression correlates with poor prognosis in patients with diverse malignancies (44). LRH-1 also regulates the extraadrenal biosynthesis of glucocorticoids, which modulate local inflammatory responses (45) and prolong the survival of neutrophils by delaying their apoptosis (46). These findings point to another possible role for LRH-1 in pancreatic tumorigenesis, through its impact on inflammatory pathways.…”

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

“…However, if the regulation of these genes indeed represents cellular antiviral defence or off-target effects, they do not seem to cause a deviant liver or ovarian phenotype in the LRH-1-KD mice. Alternatively, regulation of these pathways could be a consequence of the role of LRH-1 in immunological responses (Lin et al 2000;Mueller et al 2006;Venteclef et al 2006Venteclef et al , 2011Coste et al 2007), or an immunological response to the increase cellular debris from atretic antral follicles (Hakuno et al 1996).…”

“…Compounds modulating the activity of LRH-1 could represent an attractive new therapy for multiple indications because LRH-1 has been implicated in the inflammatory response, tumour formation, bile acid homeostasis and fertility (Botrugno et al 2004;Schoonjans et al 2005;Mueller et al 2006;Venteclef et al 2006Venteclef et al , 2011Coste et al 2007;Mataki et al 2007;Duggavathi et al 2008;Lee et al 2008;Out et al 2011). The crystal structure of LRH-1 in complex with cofactor peptides reveals the presence of phospholipids in the ligand-binding domain, indicating that the activity of LRH-1 can potentially be modulated (Ortlund et al 2005;Burendahl et al 2008).…”