Tissue-specific transcriptional regulation of the cholesterol biosynthetic pathway leads to accumulation of testis meiosis-activating sterol (T-MAS).
Lanosterol 14alpha-demethylase (CYP51) produces follicular fluid meiosis-activating sterol (FF-MAS), which is converted further to testis meiosis-activating sterol (T-MAS). MAS are intermediates in the cholesterol biosynthetic pathway, with the ability to trigger resumption of oocyte meiosis in vitro. In contrast to the liver, where pre- and post-MAS genes are upregulated coordinately at the level of transcription by a cholesterol feedback mechanism through sterol regulatory element-binding proteins (SREBP), regulation differs in the testis. Genes encoding pre-MAS enzymes [HMG-CoA synthase (SYN), HMG-CoA reductase (RED), farnesyl diphosphate synthase (FPP), squalene synthase (SS), and CYP51] are upregulated during sexual development of the testis, although not all genes are turned on at the same time. Furthermore, two post-MAS genes, C-4 sterol methyl oxidase and sterol Delta(7)-reductase, are expressed at low levels and are not upregulated either in rat or human. This transcriptional discrepancy seems to be SREBP independent. Besides cAMP/cAMP-responsive element modulator, other unknown transcription factors control expression of individual cholesterogenic genes during spermatogenesis. HPLC analysis shows an 8-fold increase in T-MAS during development of rat testis whereas MAS is barely detectable in livers of the same animals. We propose that the lack of a coordinate transcriptional control over the cholesterol biosynthetic pathway contributes importantly to overproduction of the signaling sterol T-MAS in testis.
Tacer
K Fon
KF
Institute of Biochemistry, Medical Center for Molecular Biology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
Haugen
T B
TB
Baltsen
M
M
Debeljak
N
N
Rozman
Damjana
D
D000818:Animals; D002775:Cholestadienols / Q000378:metabolism*; D002784:Cholesterol / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity / Q000235:genetics / Q000502:physiology; D010088:Oxidoreductases / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013091:Spermatogenesis / Q000235:genetics; D058886:Sterol 14-Demethylase; D013737:Testis / Q000254:growth & development / Q000378:metabolism*; D014158:Transcription, Genetic
C548418:CYP51A1 protein, human; D002775:Cholestadienols; C548417:Cyp51 protein, rat; D012333:RNA, Messenger; C071868:4,4-dimethylcholesta-8,14-dien-3-ol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase