title: The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.
abstract: Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.
authors.affiliation: Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA; School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Zhi-qiang
authors.initials: ZQ
authors.lastname: Pan
authors.affiliation: Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Xie
authors.affiliation: Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Choudhary
authors.affiliation: Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Mutsa
authors.initials: M
authors.lastname: Seremwe
authors.affiliation: Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Tsai
authors.affiliation: Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Olala
authors.affiliation: Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Xunsheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA. Electronic address: wb@gru.edu.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bollag
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis* / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C497249:DDIT3 protein, human; D004338:Drug Combinations; D005227:Fatty Acids; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000804:Angiotensin II; D051742:Transcription Factor CHOP; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; C583541:EIF2AK1 protein, human; D019892:eIF-2 Kinase; D006854:Hydrocortisone; D000077205:Pioglitazone
keywords: DDIT3; Endoplasmic reticulum stress; PPAR; Unfolded protein response; Zona glomerulosa; eIF2α