TY - JOUR
T1 - The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells
AU - Pan, Zhi qiang
AU - Xie, Ding
AU - Choudhary, Vivek
AU - Seremwe, Mutsa
AU - Tsai, Ying Ying
AU - Olala, Lawrence
AU - Chen, Xunsheng
AU - Bollag, Wendy B.
N1 - Funding Information:
Address all correspondence and requests for reprints to: Wendy B. Bollag, Ph.D., Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, Georgia 30912 (E-mail: WB@gru.edu). We appreciate the excellent technical assistance of Dr. Ismail Kaddour-Djebbar and Purnima Merai. We also thank Inas Helwa for assistance with protein assays. ZqP performed this work as a Visiting Scholar at Georgia Regents University. This study was supported by VA Merit Award #I01BX001344. WBB is supported by a VA Research Career Scientist Award. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. Appendix A
PY - 2014/8/25
Y1 - 2014/8/25
N2 - 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.
AB - 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.
KW - DDIT3
KW - EIF2α
KW - Endoplasmic reticulum stress
KW - PPAR
KW - Unfolded protein response
KW - Zona glomerulosa
UR - http://www.scopus.com/inward/record.url?scp=84926653535&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926653535&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2014.07.007
DO - 10.1016/j.mce.2014.07.007
M3 - Article
C2 - 25038520
AN - SCOPUS:84926653535
SN - 0303-7207
VL - 394
SP - 119
EP - 128
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -