Aldosterone Production in Human Adrenocortical Cells Is Stimulated by High-Density Lipoprotein 2 (HDL2) through Increased Expression of Aldosterone Synthase (CYP11B2)

• Published in: Endocrinology (Philadelphia) Vol. 152; no. 3; pp. 751 - 763
• Main Authors: Xing, Yewei, Cohen, Anthony, Rothblat, George, Sankaranarayanan, Sandhya, Weibel, Ginny, Royer, Lori, Francone, Omar L, Rainey, William E
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.03.2011
• Subjects: Adrenal Cortex - cytology; Adrenal Cortex - metabolism; Aldosterone - metabolism; Biological and medical sciences; Calcium - metabolism; Calcium Signaling - physiology; Calcium-Regulating Hormones; Cell Line; Cholesterol, HDL - pharmacology; Cytochrome P-450 CYP11B2 - genetics; Cytochrome P-450 CYP11B2 - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Humans; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Promoter Regions, Genetic; RNA, Messenger - genetics; RNA, Messenger - metabolism; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Vertebrates: endocrinology; Human; Steroid hormone; Mineralocorticoid; Adrenal hormone; Adrenal cortex; Aldosterone; Lipoprotein HDL
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-1049

HDL2 stimulates aldosterone production through the activation of calcium signaling and aldosterone synthase (CYP11B2) expression in human H295R adrenocortical cells. Adrenal aldosterone production is regulated by physiological agonists at the level of early and late rate-limiting steps. Numerous studies have focused on the role of lipoproteins including high-density lipoprotein (HDL) as cholesterol providers in this process; however, recent research suggests that HDL can also act as a signaling molecule. Herein, we used the human H295R adrenocortical cell model to study the effects of HDL on adrenal aldosterone production and CYP11B2 expression. HDL, especially HDL2, stimulated aldosterone synthesis by increasing expression of CYP11B2. HDL treatment increased CYP11B2 mRNA in both a concentration- and time-dependent manner, with a maximal 19-fold increase (24 h, 250 μg/ml of HDL). Effects of HDL on CYP11B2 were not additive with natural agonists including angiotensin II or K+. HDL effects were likely mediated by a calcium signaling cascade, because a calcium channel blocker and a calmodulin kinase inhibitor abolished the CYP11B2-stimulating effects. Of the two subfractions of HDL, HDL2 was more potent than HDL3 in stimulating aldosterone and CYP11B2. Further studies are needed to identify the active components of HDL, which regulate aldosterone production.