Transforming growth factor beta1 decreases cholesterol supply to mitochondria via repression of steroidogenic acute regulatory protein expression.
Transforming growth factor-betas (TGF-betas) constitute a family of dimeric proteins that affect growth and differentiation of many cell types. TGF-beta1 has also been proposed to be an autocrine regulator of adrenocortical steroidogenesis, acting mainly by decreasing the expression of cytochrome P450c17. Here, we demonstrate that TGF-beta1 has a second target in bovine adrenocortical cells, namely the steroidogenic acute regulatory protein (StAR). Indeed, supplying cells with steroid precursors revealed that TGF-beta1 inhibited two steps in the steroid synthesis pathway, one prior to pregnenolone production and another corresponding to P450c17. More specifically, TGF-beta1 inhibited pregnenolone production but neither the conversion of 25-hydroxycholesterol to pregnenolone nor P450scc activity. Thus, TGF-beta1 must decrease the cholesterol supply to P450scc. We therefore examined the effect of TGF-beta1 on the expression of StAR, a mitochondrial protein implicated in intramitochondrial cholesterol transport. TGF-beta1 decreased the steady state level of StAR mRNA in a time- and concentration-dependent manner. This inhibition occurs at the level of StAR transcription and depends on RNA and protein synthesis. It is likely that the TGF-beta1- induced decrease of StAR expression that we report here may be expanded to other steroidogenic cells in which a decrease of cholesterol accessibility to P450scc by TGF-beta1 has been hypothesized.[1]References
- Transforming growth factor beta1 decreases cholesterol supply to mitochondria via repression of steroidogenic acute regulatory protein expression. Brand, C., Cherradi, N., Defaye, G., Chinn, A., Chambaz, E.M., Feige, J.J., Bailly, S. J. Biol. Chem. (1998) [Pubmed]
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