Hormonal Regulation of Testicular Steroid and Cholesterol Homeostasis

Abstract

The male sex steroid, testosterone (T), is synthesized from cholesterol in the testicular Leydig cell under control of the pituitary gonadotropin LH. Unlike most cells that use cholesterol primarily for membrane synthesis, steroidogenic cells have additional requirements for cholesterol, because it is the essential precursor for all steroid hormones. Little is known about how Leydig cells satisfy their specialized cholesterol requirements for steroid synthesis. We show that in mice with a unique hypomorphic androgen mutation, which disrupts the feedback loop governing T synthesis, that genes involved in cholesterol biosynthesis/uptake and steroid biosynthesis are up-regulated. We identify LH as the central regulatory molecule that controls both steroidogenesis and Leydig cell cholesterol homeostasis in vivo. In addition to the primary defect caused by high levels of LH, absence of T signaling exacerbates the lipid homeostasis defect in Leydig cells by eliminating a short feedback loop. We show that T signaling can affect the synthesis of steroids and modulates the expression of genes involved in de novo cholesterol synthesis. Surprisingly, accumulation of active sterol response element-binding protein 2 is not required for up-regulation of genes involved in cholesterol biosynthesis and uptake in Leydig cells.

Gonadotropin-regulated Testicular RNA Helicase (GRTH/DDX25), a Negative Regulator of Luteinizing/Chorionic Gonadotropin Hormone-induced Steroidogenesis in Leydig Cells

“…The finding of no change in the SREBP2-targeted HMGCR gene expression at the mRNA level (Fig. 3) supports early studies showing the lack of a regulatory role of SREBP2 in cholesterol synthesis in Leydig cells (16). However, the role of SREBP2 in cholesterol formation in Leydig cells require further studies, and the GRTH Ϫ/Ϫ model may be appropriate for this purpose.…”

“…Although SREBP2 as a transcription factor is known to activate genes involved in the cholesterol biosynthetic pathway and receptor-mediated cholesterol uptake (17) in most mammalian cells, this may not be the case for gonadal steroidogenesis. Studies in mouse Leydig cells revealed that cAMP-stimulated expression of genes involved in cholesterol synthesis is independent of the nuclear recruitment of SREBP2 (16). In the case of GRTH null mice, the significantly up-regulated SREBP2 expression (Figs.…”

SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP

“…cAMP elevation and PKA activation are known to stimulate several critical steps in steroid production (42). PKA activation leads to activation of HSL (5,43), which releases cholesterol and free fatty acids from cholesteryl ester storage and perhaps other sites in the cell.…”

Developmental Expression and Endocrine Regulation of CYP1B1 in Rat Testis

“…Hypophysectomy results in decreased CYP17A1 expression, but the levels were increased by treatment with exogenous LH but not FSH (Takeyama et al, 1986). The molecular basis by which LH induced CYP1B1 protein levels is not clear at this time, but it may involve LH receptor activation and increased intracellular levels of cAMP, which is the mechanism by which LH increases expression of genes encoding P450 enzymes involved in androgen synthesis (Eacker et al, 2008).…”

“…Testosterone acting through the androgen receptor is needed for normal development of the testis (Haider, 2004). Previous studies showed that treatment of intact rats with high dosages of testosterone reduces LH secretion from the pituitary, represses transcription of genes involved in steroidogenesis, including CYP17A1 and CYP11A1, and inhibits spermatogenesis (Keeney and Ewing, 1990;Eacker et al, 2008). Treatment of adult hypophysectomized rats with testosterone can partially restore spermatogenesis, but it had little effect on Leydig cell proliferation or function (Keeney and Ewing, 1990).…”