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.
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Commissariat 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.
Cherradi
N
N
Defaye
G
G
Chinn
A
A
Chambaz
E M
EM
Feige
J J
JJ
Bailly
S
S
D000818:Animals; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D005786:Gene Expression Regulation; D006854:Hydrocortisone / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D011284:Pregnenolone / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015383:Zona Fasciculata / Q000166:cytology / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D012333:RNA, Messenger; D013256:Steroids; D016212:Transforming Growth Factor beta; D000098682:Steroidogenic Acute Regulatory Protein; D011284:Pregnenolone; D002784:Cholesterol; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D006854:Hydrocortisone