Transforming growth factor β1 decreases cholesterol supply to mitochondria via repression of steroidogenic acute regulatory protein expression

Abstract

Transforming growth factor-βs (TGF-βs) constitute a family of dimeric proteins that affect growth and differentiation of many cell types. TGF-β1 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-β1 has a second target in bovine adrenocortical cells, namely the steroidogenic acute regulatory protein (StAR). Indeed, supplying cells with steroid precursors revealed that TGF- β1 inhibited two steps in the steroid synthesis pathway, one prior to pregnenolone production and another corresponding to P450c17. More specifically, TGF-β1 inhibited pregnenolone production but neither the conversion of 25-hydroxycholesterol to pregnenolone nor P450scc activity. Thus, TGF-β1 must decrease the cholesterol supply to P450scc. We therefore examined the effect of TGF-β1 on the expression of StAR, a mitochondrial protein implicated in intramitochondrial cholesterol transport. TGF-β1 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-β1- 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-β1 has been hypothesized.