Hormonal regulation of testicular steroid and cholesterol homeostasis.
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.
Eacker
Stephen M
SM
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Agrawal
Nalini
N
Qian
Kun
K
Dichek
Helén L
HL
Gong
Eun-Yeung
EY
Lee
Keesook
K
Braun
Robert E
RE
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D007985:Leydig Cells / Q000166:cytology / Q000378:metabolism; D007986:Luteinizing Hormone / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D051379:Mice; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood; D015854:Up-Regulation
D012333:RNA, Messenger; D011944:Receptors, Androgen; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051122:Scavenger Receptors, Class B; D051782:Sterol Regulatory Element Binding Protein 2; D013739:Testosterone; D007986:Luteinizing Hormone; D002784:Cholesterol; D000242:Cyclic AMP; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C039306:sterol delta-5 desaturase; C019995:7-dehydrocholesterol reductase