title: A cell-autonomous molecular cascade initiated by AMP-activated protein kinase represses steroidogenesis.
abstract: 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.
authors.affiliation: Reproduction, Mother and Child Health, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec City, Québec, Canada.
authors.forename: Houssein S
authors.initials: HS
authors.lastname: Abdou
authors.affiliation: Reproduction, Mother and Child Health, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec City, Québec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Bergeron
authors.affiliation: Reproduction, Mother and Child Health, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec City, Québec, Canada Centre for Research in Biology of Reproduction, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, Québec, Canada Jacques-J.Tremblay@crchul.ulaval.ca.
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Tremblay
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000096:biosynthesis; D000311:Adrenal Glands / Q000166:cytology; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors; D004734:Energy Metabolism / Q000502:physiology; D007985:Leydig Cells / Q000166:cytology; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis*; D010766:Phosphorylation; D011374:Progesterone / Q000096:biosynthesis* / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis; D054339:Steroidogenic Factor 1 / Q000096:biosynthesis; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D054339:Steroidogenic Factor 1; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D013739:Testosterone; D000249:Adenosine Monophosphate; D011374:Progesterone; D007986:Luteinizing Hormone; D002784:Cholesterol; D000242:Cyclic AMP; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C548179:Prkaa1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C520790:Pde8a protein, mouse