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Báo cáo khoa học: Silencing the expression of mitochondrial acyl-CoA thioesterase I and acyl-CoA synthetase 4 inhibits hormone-induced steroidogenesis

Arachidonic acid and its lypoxygenated metabolites play a fundamental role in the hormonal regulation of steroidogenesis. Reduction in the expres-sion of the mitochondrial acyl-CoA thioesterase (MTE-I) by antisense or small interfering RNA (siRNA) and of the arachidonic acid-preferring acyl-CoA synthetase (ACS4) by siRNA produced a marked reduction in steroid output of cAMP-stimulated Leydig cells. | iFEBS Journal Silencing the expression of mitochondrial acyl-CoA thioesterase I and acyl-CoA synthetase 4 inhibits hormone-induced steroidogenesis Paula Maloberti Rocio Castilla Fernanda Castillo Fabiana Cornejo Maciel Carlos F. Mendez Cristina Paz and Ernesto J. Podesta Department of Biochemistry Schoolof Medicine University of Buenos Aires Argentina Keywords ACS4 acyl-CoA arachidonic acid mitochondrialacyl-CoA thioesterase I MTE-I steroidogenesis Correspondence E. J. Podesta Depto. de Bioquimica Facultad de Medicina Paraguay 2155 piso 5 C1121ABG Buenos Aires Argentina Tel Fax 54 11 4508 3672 ext. 31 E-mail biohrdc@fmed.uba.ar Note These authors contributed equally to this work Received 27 October 2004 revised 9 February 2005 accepted 16 February 2005 doi 10.1111 j.1742-4658.2005.04616.x Arachidonic acid and its lypoxygenated metabolites play a fundamental role in the hormonal regulation of steroidogenesis. Reduction in the expression of the mitochondrial acyl-CoA thioesterase MTE-I by antisense or small interfering RNA siRNA and of the arachidonic acid-preferring acyl-CoA synthetase ACS4 by siRNA produced a marked reduction in steroid output of cAMP-stimulated Leydig cells. This effect was blunted by a permeable analog of cholesterol that bypasses the rate-limiting step in steroidogenesis the transport of cholesterol from the outer to the inner mitochondrial membrane. The inhibition of steroidogenesis was overcome by addition of exogenous arachidonic acid indicating that the enzymes are part of the mechanism responsible for arachidonic acid release involved in steroidogenesis. Knocking down the expression of MTE-I leads to a significant reduction in the expression of steroidogenic acute regulatory protein. This protein is induced by arachidonic acid and controls the rate-limiting step. Overexpression of MTE-I resulted in an increase in cAMP-induced steroidogenesis. In summary our results demonstrate a critical role for ACS4 and MTE-I in the hormonal regulation of