The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells

Zhi qiang Pan, Ding Xie, Vivek Choudhary, Mutsa Seremwe, Ying Ying Tsai, Lawrence Olala, Xunsheng Chen, Wendy B Bollag

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)119-128
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume394
Issue number1-2
DOIs
StatePublished - Aug 25 2014

Fingerprint

pioglitazone
Adrenocortical Carcinoma
Aldosterone
Hydrocortisone
Cells
Cytochrome P-450 CYP11B2
Angiotensin II
Unfolded Protein Response
Thiazolidinediones
Peroxisome Proliferator-Activated Receptors
Proteins
Fluids
Translational Peptide Chain Initiation
Fatty Acids
Steroid 11-beta-Hydroxylase
Steroid hormones
Aptitude
Lipolysis
Protein Biosynthesis
Medical problems

Keywords

  • DDIT3
  • EIF2α
  • Endoplasmic reticulum stress
  • PPAR
  • Unfolded protein response
  • Zona glomerulosa

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells. / Pan, Zhi qiang; Xie, Ding; Choudhary, Vivek; Seremwe, Mutsa; Tsai, Ying Ying; Olala, Lawrence; Chen, Xunsheng; Bollag, Wendy B.

In: Molecular and Cellular Endocrinology, Vol. 394, No. 1-2, 25.08.2014, p. 119-128.

Research output: Contribution to journalArticle

Pan, Zhi qiang ; Xie, Ding ; Choudhary, Vivek ; Seremwe, Mutsa ; Tsai, Ying Ying ; Olala, Lawrence ; Chen, Xunsheng ; Bollag, Wendy B. / The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells. In: Molecular and Cellular Endocrinology. 2014 ; Vol. 394, No. 1-2. pp. 119-128.
@article{bc6ad26970dc450581163db197699009,
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.",
keywords = "DDIT3, EIF2α, Endoplasmic reticulum stress, PPAR, Unfolded protein response, Zona glomerulosa",
author = "Pan, {Zhi qiang} and Ding Xie and Vivek Choudhary and Mutsa Seremwe and Tsai, {Ying Ying} and Lawrence Olala and Xunsheng Chen and Bollag, {Wendy B}",
year = "2014",
month = "8",
day = "25",
doi = "10.1016/j.mce.2014.07.007",
language = "English (US)",
volume = "394",
pages = "119--128",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",
number = "1-2",

}

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

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

VL - 394

SP - 119

EP - 128

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

IS - 1-2

ER -