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

K. Fon Tacer, T. B. Haugen, M. Baltsen, N. Debeljak, D. Rozman

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Lanosterol 14α-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 Δ7-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.

Original languageEnglish (US)
Pages (from-to)82-89
Number of pages8
JournalJournal of lipid research
Volume43
Issue number1
StatePublished - Feb 12 2002

Keywords

  • Cholesterol biosynthesis
  • Cytochrome P450
  • Lanosterol 14α-demethylase
  • Spermatogenesis and meiosis-activating sterol

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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