- Publication date : 2014-10-30
Abdou HS, Bergeron F, Tremblay JJ. A cell-autonomous molecular cascade initiated by AMP-activated protein kinase represses steroidogenesis. Mol. Cell. Biol. 2014;34:4257-71. doi: 10.1128/MCB.00734-14. PubMed PMID: 25225331.
3',5'-cyclic-amp phosphodiesterases amp-activated protein kinases adenosine monophosphate adrenal glands animals biological transport cell line, tumor cholesterol cyclic amp e1a-associated p300 protein energy metabolism leydig cells luteinizing hormone male mice mice, knockout nuclear receptor subfamily 4, group a, member 1 phosphoproteins phosphorylation progesterone protein-serine-threonine kinases rna interference rna, small interfering scavenger receptors, class b steroidogenic factor 1 testosterone
Steroid hormones regulate essential physiological processes, and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by luteinizing hormone (LH) via its receptor leading to increased cyclic AMP (cAMP) production and expression of the steroidogenic acute regulatory (STAR) protein, which is essential for the initiation of steroidogenesis. Steroidogenesis then passively decreases with the degradation of cAMP into AMP by phosphodiesterases. In this study, we show that AMP-activated protein kinase (AMPK) is activated following cAMP-to-AMP breakdown in MA-10 and MLTC-1 Leydig cells. Activated AMPK then actively inhibits cAMP-induced steroidogenesis by repressing the expression of key regulators of steroidogenesis, including Star and Nr4a1. Similar results were obtained in Y-1 adrenal cells and in the constitutively steroidogenic R2C cells. We have also determined that maximum AMPK activation following stimulation of steroidogenesis in MA-10 Leydig cells occurs when steroid hormone production has reached a plateau. Our data identify AMPK as a molecular rheostat that actively represses steroid hormone biosynthesis to preserve cellular energy homeostasis and prevent excess steroid production.