In vivo inhibition of steroidogenic acute regulatory protein expression by dexamethasone parallels induction of the negative transcription factor DAX-1.
In this study, we investigated the effect of dexamethasone on the synthesis of steroidogenic acute regulatory protein (StAR) and the expression of DAX-1 (dosage sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1) and SF-1 (steroidogenic factor-1) in vivo. Male rats were treated with dexamethasone (0.4 and 4 mg/kg body wt per day) by intraperitoneal injections using phosphate-buffered saline as the vehicle for 7 d. At the end of 7 d, serum testosterone levels were decreased. Response to luteinizing hormone (LH) and 8-bromo-cyclic-AMP (8-Br-cAMP) in vitro was reduced in testicular cells isolated from dexamethasone-treated rat testes. Dexamethasone decreased LH-stimulated cAMP production. The conversion of 22(R)-hydroxycholesterol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, and androstenedione to testosterone was not affected by dexamethasone. Dexamethasone increased DAX-1 expression and concordantly decreased StAR protein and mRNA in testicular cells. The increase in DAX-1 protein corresponded to a 57% reduction in StAR mRNA levels concomitant with a 79% reduction in serum testosterone levels. Dexamethasone had no effect on the level of SF-1, but increased the amount of complexed DAX-1-SF-1. Dexamethasone in vitro suppressed StAR promoter activity when an increasing amount of DAX-1 cDNA was transfected. These results demonstrate that dexamethasone increases expression of DAX-1, which results in increased amounts of complexed DAX-1-SF-1, in the absence of any change in the expression of SF-1. These observations strongly support the concept that dexamethasone suppresses rat testicular testosterone production, at least in part, by increasing the amount of complexed DAX-1-SF-1 in these cells, which leads directly to decreased availability of free SF-1 and, therefore, decreased activation of transcription of the rat StAR gene.
Yu
Chi-Chuan
CC
Department of Physiology, National Cheng Kung University College of Medicine, Tainan 70101, Taiwan, Republic of China.
Li
Pi-Hsueh S
PH
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D057137:DAX-1 Orphan Nuclear Receptor; D018076:DNA, Complementary / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D054339:Steroidogenic Factor 1; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
D057137:DAX-1 Orphan Nuclear Receptor; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D018398:Homeodomain Proteins; C539967:Nr0b1 protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; C515060:steroidogenic factor 1, rat; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013739:Testosterone; D003907:Dexamethasone