HORMONAL REGULATION OF ARACHIDONIC ACID RELEASE IN A SPECIFIC COMPARTMENT OF THE CELL

F. CASTILLO; F. CORNEJO MACIEL; R. CASTILLA; P. MALOBERTI; A. DUARTE; F. TOLEDO; F. MEULI; C. PAZ; E.J. PODESTÁ

Boston, MA, USA

Conferencia; XIIth Adrenal Cortex and Vth Molecular Steroidogenesis Conference; 2006

Previously we showed a new mechanism that controls the level of free AA. This hormone regulated mechanism involves the concerted action of two enzymes, an acyl-CoA synthetase and an acyl-CoA thioesterase. The synthetase, named ACS4, was described as an AA preferring enzyme that is preferentially expressed in steroidogenic tissues. The thioesterase is a member of a family with long chain fatty acyl-CoA thioesterase activity which is associated with the inner mitochondrial membrane, named Acot2. The steroidogenic hormones regulate both enzymes: while Acot2 is activated by phosphorylation and substrate availability, ACS4 is rapidly induced after hormone treatment. The participation of ACS4 and Acot2 as obligatory components of AA release, StAR induction and steroidogenesis was confirmed by recent experiments showing that steroid production is inhibited in Y1 and MA-10 cells by silencing the expression of both, Acot2 or ACS4. These results led us to propose that ACS4 acts by sequestering free AA forming an intracellular pool of AA-CoA that is delivered to Acot2 which will, in turn, release AA in a specific compartment of the ceil (the mitochondria). In the present report we demonstrate that in the acute phase (early response) of steroid synthesis, the release of AA into the mitochondria is stimulated by cAMP and it is able to increase cholesterol transport.