TRANSFORMING-GROWTH-FACTOR BETA(1) DECREASES CHOLESTEROL SUPPLY TO MITOCHONDRIA VIA REPRESSION OF STEROIDOGENIC ACUTE REGULATORY PROTEIN EXPRESSION

Transforming growth factor-beta s (TGF-beta s) constitute a family of dimeric proteins that affect growth and differentiation of many cell t ypes, TGF-beta(1) has also been proposed to be an autocrine regulator of adrenocortical steroidogenesis, acting mainly by decreasing the exp ression of cytochrome P450c17. Here, we demonstrate that TGF-beta(1) h as a second target in bovine adrenocortical cells, namely the steroido genic acute regulatory protein (StAR). Indeed, supplying cells with st eroid precursors revealed that TGF-beta(1) inhibited two steps in the steroid synthesis pathway, one prior to pregnenolone production and an other corresponding to P450c17. More specifically, TGF-beta(1) inhibit ed pregnenolone production but neither the conversion of 25-hydroxycho lesterol to pregnenolone nor P450scc activity. Thus, TGF-beta(1) must decrease the cholesterol supply to P450scc. We therefore examined the effect of TGF-beta(1) on the expression of StAR, a mitochondrial prote in implicated in intramitochondrial cholesterol transport, TGF-beta(1) decreased the steady state level of StAR mRNA in a time- and concentr ation-dependent manner. This inhibition occurs at the level of StAR tr anscription and depends on RNA and protein synthesis. It is likely tha t the TGF-beta(1)-induced decrease of StAR expression that we report h ere may be expanded to other steroidogenic cells in which a decrease o f cholesterol accessibility to P450scc by TGF-beta(1) has been hypothe sized.