AN ACYL-COA SYNTHETASE AND MITOCHONDRIAL ARACHIDONIC ACID AS KEY REGULATOR OF NEUROSTEROIDOGENESIS

ORLANDO ULISES; MILD JESICA; PEREZ MARÍA JULIA; SCAZZINA BRENDA; PASQUINI JUANA MARÍA; PODESTA, ERNESTO J; MALOBERTI PAULA

Tucuman

Congreso; XLVI Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2009

Saib

Stimulation of receptors and subsequent signal transduction results in the activation of arachidonic acid (AA) release and metabolism via the cycloxygenase, lipoxygenase or epoxygenase (citochrome P-450) pathways. How the cells drive AA to these pathways is not elucidated yet. Our laboratory showed a new mechanism that controls the level of free AA in adrenal, testis, heart and malignant cells. The hormone regulated mechanism involves the concerted action of acyl-CoA synthetase (Acsl4) and a mitochondrial acyl-CoA thioesterase (Acot2). Thus, generating AA, that serves as substrate of the lipoxygenase enzymes to regulate the steroidogenic acute regulatory (StAR) protein and cholesterol transport in the mitochondria, the rate-limiting step in steroid biosynthesis. It is known that the brain is also a steroidogenic tissue; however the transduction mechanism that controls the synthesis of neurosteroids is still unknown. To study this mechanism, we used as model primary culture of astrocytes from 2 days-old cerebellum which is known to express StAR protein under cAMP regulation. We demonstrate by RT-PCR, immunohistochemistry and Western blot that Acsl4 and Acot2 are expressed in astrocytes and that this expression is regulated by cAMP in parallel with the induction of StAR. In accordance with these findings, lipoxygenase inhibitors regulate the StAR protein induction.