Valproic acid alters mitochondrial cholesterol transport in Y1 adrenocortical cells.
Several reports suggest putative interactions between valproic acid (VPA) treatment and the hypothalamus-pituitary-adrenal axis. Given that VPA alters mitochondrial functions, an action of this drug on a mitochondrial process such as steroid synthesis in adrenal cells should be expected. In order to disclose a putative action of VPA on the adrenocortical cell itself we evaluated VPA effects on regulatory steps of the acute stimulation of steroidogenesis in Y1 adrenocortical cells. This study demonstrates that VPA increases progesterone production in non-stimulated cells without inducing the levels of Steroidogenic Acute Regulatory (StAR) protein, which facilitates cholesterol transport. This result suggests that VPA increases mitochondrial cholesterol transport through a StAR-independent mechanism and is further supported by the fact that in isolated mitochondria VPA stimulates exogenous cholesterol metabolization to progesterone. VPA also reduces the cAMP-mediated increase of the StAR protein, mRNA levels, promoter activity and progesterone production. In summary, the present data show that VPA can alter steroid production in adrenal cells by a complex mechanism that mainly involves an action on cholesterol access to the inner mitochondrial membrane. The VPA-mediated increase of basal steroidogenesis could be linked to the increase of basal cortisolemia described in patients under VPA treatment.
Brion
L
L
IIHMNO-Department of Biochemistry, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Gorostizaga
A
A
Gómez
N V
NV
Podestá
E J
EJ
Cornejo Maciel
F
F
Paz
C
C
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000819:agonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000633:toxicity; D000098682:Steroidogenic Acute Regulatory Protein
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D014635:Valproic Acid; D002784:Cholesterol; D000242:Cyclic AMP; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme