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Journal of Lipid Research, Vol. 43, 82-89, January 2002
Copyright © 2002 by Lipid Research, Inc.

Tissue-specific transcriptional regulation of the cholesterol biosynthetic pathway leads to accumulation of testis meiosis-activating sterol (T-MAS)

Correspondence to: D. Rozman, To whom correspondence should be addressed., damjana.rozman{at}mf.uni-lj.si (E-mail)

Lanosterol 14-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 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. — Fon Tacer, K., T. B. Haugen, M. Baltsen, N. Debeljak, and D. Rozman. Tissue-specific transcriptional regulation of the cholesterol biosynthetic pathway leads to accumulation of testis meiosis-activating sterol (T-MAS). J. Lipid Res. 2002. 43: 82–89.

Supplementary key words: cholesterol biosynthesis, cytochrome P450, lanosterol 14-demethylase, spermatogenesis and meiosis-activating sterol

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