Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells

Abstract

a b s t r a c tNeurosteroids are involved in Central Nervous System development, brain functionality and neuroprotection but little is known about regulators of their biosynthesis. Recently gonadotropins, Gonadotropin-releasing Hormone (GnRH) and their receptors have been localized in different brain regions, such as hippocampus and cortex.Using human neuronal-like cells we found that GnRH up-regulates the expression of key genes of cholesterol and steroid synthesis when used in a narrow range around 1.0 nM. The expression of Hydroxysterol D24-reductase (seladin-1/DHCR24), that catalyzes the last step of cholesterol biosynthesis, is increased by 50% after 90 min of incubation with GnRH. StAR protein and P450 side chain cleavage (P450scc) are up-regulated by 3.3 times after 90 min and by 3.5 times after 3 h, respectively. GnRH action is mediated by LH and 1.0 nM GnRH enhances the expression of LH␤ as well.A two fold increase of cell cholesterol is induced after 90 min of GnRH incubation and 17␤-estradiol (E2) production is increased after 24, 48 and 72 h. These data indicate for the first time that GnRH regulates both cholesterol and steroid biosynthesis in human neuronal-like cells and suggest a new physiological role for GnRH in the brain.

Perimenopausal regulation of steroidogenesis in the nonhuman primate

“…There is evidence of age-related promoter damage that leads to down-regulation of certain genes (Lu et al, 2004), which may explain the lack of steroidogenic regulation in the oldest animals. Additionally, as local E 2 synthesis has been shown to be regulated by GnRH input to the hippocampus (Prange-Kiel et al, 2008; Prange-Kiel et al, 2009; Rosati et al, 2011), a dysregulation of GnRH signaling, or reduced GnRH responsiveness with age or ovariectomy, may further modulate steroidogenic enzyme expression. The present observation that exogenous E 2 down-regulates neurosteroidogenic enzyme expression is consistent with a previous study demonstrating E 2 treatment of ovariectomized rhesus macaques results in a decrease in GnRH pulse amplitude (Mizuno and Terasawa, 2005); thus, peripheral or exogenous E 2 may downregulate local hippocampal steroidogenesis via GnRH suppression.…”

Acrosome reaction is impaired in spermatozoa of obese men: a preliminary study

“…The amount of cholesterol was determined by gas chromatography/mass spectrometry (GC/MS) as previously described (20). Briefly, spermatozoa obtained from 1 mL of seminal plasma after 2 washes in PBS were lysed in 1 N NaOH and stored at À20 C. Sample protein concentration in the lysates was determined by Coomassie staining.…”

Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats

“…In the present studies, GnRH is proposed to impact memory by acting in the hippocampus to regulate neuroestradiol synthesis. A possible mechanism by which GnRH regulates neuroestradiol synthesis is through increasing levels of steroid acute regulatory protein (StAR), which initiates neurosteroid synthesis (Rosati et al, 2011). Further, GnRH is able to directly stimulate estradiol synthesis in ovarian granulosa cells (Janssens et al, 2000), and activation of GnRH receptors increases estradiol synthesis in the hippocampus, impacting dendritic spine density and levels of synaptic proteins (Fester et al, 2012; Prange-Kiel et al, 2013).…”