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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
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Transforming growth factor beta1 decreases cholesterol supply to mitochondria via repression of steroidogenic acute

C Brand1, N Cherradi, G Defaye

  • 1Commissariat à l'Energie Atomique, Département de Biologie Moléculaire et Structurale, Biochìmìe des Régulations Cellulaires Endocrines, INSERM Unité 244, 17 rue des Martyrs, F-38054 Grenoble, France.

The Journal of Biological Chemistry
|April 16, 1998
PubMed

Insights

Transforming growth factor-beta1 (TGF-beta1) inhibits steroidogenesis in bovine adrenocortical cells by decreasing steroidogenic acute regulatory protein (StAR) expression. This novel finding reveals a second TGF-beta1 target, impacting cholesterol transport and steroid production.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Transforming growth factor-betas (TGF-betas) are proteins regulating cell growth and differentiation.
  • TGF-beta1 is implicated as an autocrine regulator of adrenocortical steroidogenesis, primarily by reducing cytochrome P450c17 expression.

Purpose of the Study:

  • To investigate the effects of TGF-beta1 on steroidogenesis in bovine adrenocortical cells.
  • To identify additional targets of TGF-beta1 beyond cytochrome P450c17 in the steroidogenic pathway.

Main Methods:

  • Bovine adrenocortical cells were treated with TGF-beta1 in the presence of steroid precursors.
  • Steroid production, including pregnenolone, was measured.
  • The expression of steroidogenic acute regulatory protein (StAR) mRNA was analyzed using quantitative methods.
  • Transcriptional regulation of StAR was assessed, considering RNA and protein synthesis dependency.

Main Results:

  • TGF-beta1 inhibited steroid synthesis at two key steps: one before pregnenolone production and another involving P450c17.
  • Specifically, TGF-beta1 reduced pregnenolone production without affecting 25-hydroxycholesterol conversion or P450scc activity, indicating reduced cholesterol supply to P450scc.
  • TGF-beta1 significantly decreased StAR mRNA levels in a time- and dose-dependent manner.
  • The inhibition of StAR expression was found to occur at the transcriptional level and required ongoing RNA and protein synthesis.

Conclusions:

  • TGF-beta1 exerts its inhibitory effect on steroidogenesis by targeting StAR expression in bovine adrenocortical cells.
  • This action reduces the transport of cholesterol to cytochrome P450scc, thereby decreasing steroid production.
  • The findings suggest that TGF-beta1's impact on StAR expression may be relevant in other steroidogenic cells where reduced cholesterol accessibility to P450scc is hypothesized.

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