Acute and long-term effects of arsenite in HepG2 cells: Modulation of insulin signaling

Ingrit Hamann, Kerstin Petroll, Xiaoqing Hou, Anwar Anwar-Mohamed, Ayman O S El-Kadi, Lars Oliver Klotz

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Epidemiological studies have indicated a relationship between the prevalence of diabetes and exposure to arsenic. Mechanisms by which arsenic may cause this diabetogenic effect are largely unknown. The phosphoinositide 3′-kinase (PI3K)/Akt signaling pathway plays an important role in insulin signaling by controlling glucose metabolism, in part through regulating the activity of FoxO transcription factors. The present study aimed at investigating the effect of short and long-term exposure to arsenite on insulin signaling in HepG2 human hepatoma cells, the role of PI3K/Akt signaling therein and the modulation of target genes controlled by insulin. Exposure of cells to arsenite for 24 h rendered cells less responsive toward stimulation of Akt by insulin. At the same time, short-term exposure to arsenite induced a concentration- dependent increase in phosphorylation of Akt at Ser-473, followed by phosphorylation of FoxO proteins at sites known to be phosphorylated by Akt. Phosphorylation of FoxOs was prevented by wortmannin, pointing to the involvement of PI3K. Arsenite exposure resulted in attenuation of FoxO DNA binding and in nuclear exclusion of FoxO1a-EGFP. A 24-h exposure of HepG2 cells to submicromolar concentrations of arsenite resulted in downregulation of glucose 6-phosphatase (G6Pase) and selenoprotein P (SelP) mRNA levels. Curiously, arsenite had a dual effect on SelP protein levels, inducing a small increase in the nanomolar and a distinct decrease in the micromolar concentration range. Interestingly, arsenite-induced long-term effects on G6Pase and SelP mRNA or SelP protein levels were not blocked by the PI3K inhibitor, wortmannin. In conclusion, arsenite perturbs cellular signaling pathways involved in fuel metabolism: it impairs cellular responsiveness toward insulin, while at the same time stimulating insulin-like signaling to attenuate the expression of genes involved in glucose metabolism and the release of the hepatokine SelP, which is known to modulate peripheral insulin sensitivity.

LanguageEnglish
Pages317-332
Number of pages16
JournalBioMetals
Volume27
Issue number2
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

arsenites
Insulin
Hep G2 Cells
Selenoprotein P
long term effects
selenoproteins
insulin
Modulation
1-Phosphatidylinositol 4-Kinase
phosphatidylinositol 3-kinase
Phosphorylation
Phosphatidylinositols
Glucose
Metabolism
Phosphotransferases
cells
glucose-6-phosphatase
Phosphatases
Glucose-6-Phosphatase
Proteins

Keywords

  • Akt
  • Arsenic
  • FoxO transcription factors
  • HepG2 cells
  • Insulin signaling
  • Selenium homeostasis

Cite this

Hamann, I., Petroll, K., Hou, X., Anwar-Mohamed, A., El-Kadi, A. O. S., & Klotz, L. O. (2014). Acute and long-term effects of arsenite in HepG2 cells: Modulation of insulin signaling. BioMetals, 27(2), 317-332. https://doi.org/10.1007/s10534-014-9714-y
Hamann, Ingrit ; Petroll, Kerstin ; Hou, Xiaoqing ; Anwar-Mohamed, Anwar ; El-Kadi, Ayman O S ; Klotz, Lars Oliver. / Acute and long-term effects of arsenite in HepG2 cells : Modulation of insulin signaling. In: BioMetals. 2014 ; Vol. 27, No. 2. pp. 317-332.
@article{126e5149f390471ba422c993bf6ef342,
title = "Acute and long-term effects of arsenite in HepG2 cells: Modulation of insulin signaling",
abstract = "Epidemiological studies have indicated a relationship between the prevalence of diabetes and exposure to arsenic. Mechanisms by which arsenic may cause this diabetogenic effect are largely unknown. The phosphoinositide 3′-kinase (PI3K)/Akt signaling pathway plays an important role in insulin signaling by controlling glucose metabolism, in part through regulating the activity of FoxO transcription factors. The present study aimed at investigating the effect of short and long-term exposure to arsenite on insulin signaling in HepG2 human hepatoma cells, the role of PI3K/Akt signaling therein and the modulation of target genes controlled by insulin. Exposure of cells to arsenite for 24 h rendered cells less responsive toward stimulation of Akt by insulin. At the same time, short-term exposure to arsenite induced a concentration- dependent increase in phosphorylation of Akt at Ser-473, followed by phosphorylation of FoxO proteins at sites known to be phosphorylated by Akt. Phosphorylation of FoxOs was prevented by wortmannin, pointing to the involvement of PI3K. Arsenite exposure resulted in attenuation of FoxO DNA binding and in nuclear exclusion of FoxO1a-EGFP. A 24-h exposure of HepG2 cells to submicromolar concentrations of arsenite resulted in downregulation of glucose 6-phosphatase (G6Pase) and selenoprotein P (SelP) mRNA levels. Curiously, arsenite had a dual effect on SelP protein levels, inducing a small increase in the nanomolar and a distinct decrease in the micromolar concentration range. Interestingly, arsenite-induced long-term effects on G6Pase and SelP mRNA or SelP protein levels were not blocked by the PI3K inhibitor, wortmannin. In conclusion, arsenite perturbs cellular signaling pathways involved in fuel metabolism: it impairs cellular responsiveness toward insulin, while at the same time stimulating insulin-like signaling to attenuate the expression of genes involved in glucose metabolism and the release of the hepatokine SelP, which is known to modulate peripheral insulin sensitivity.",
keywords = "Akt, Arsenic, FoxO transcription factors, HepG2 cells, Insulin signaling, Selenium homeostasis",
author = "Ingrit Hamann and Kerstin Petroll and Xiaoqing Hou and Anwar Anwar-Mohamed and El-Kadi, {Ayman O S} and Klotz, {Lars Oliver}",
year = "2014",
doi = "10.1007/s10534-014-9714-y",
language = "English",
volume = "27",
pages = "317--332",
journal = "Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine",
issn = "0966-0844",
publisher = "Springer, Springer Nature",
number = "2",

}

Hamann, I, Petroll, K, Hou, X, Anwar-Mohamed, A, El-Kadi, AOS & Klotz, LO 2014, 'Acute and long-term effects of arsenite in HepG2 cells: Modulation of insulin signaling', BioMetals, vol. 27, no. 2, pp. 317-332. https://doi.org/10.1007/s10534-014-9714-y

Acute and long-term effects of arsenite in HepG2 cells : Modulation of insulin signaling. / Hamann, Ingrit; Petroll, Kerstin; Hou, Xiaoqing; Anwar-Mohamed, Anwar; El-Kadi, Ayman O S; Klotz, Lars Oliver.

In: BioMetals, Vol. 27, No. 2, 2014, p. 317-332.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Acute and long-term effects of arsenite in HepG2 cells

T2 - Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine

AU - Hamann, Ingrit

AU - Petroll, Kerstin

AU - Hou, Xiaoqing

AU - Anwar-Mohamed, Anwar

AU - El-Kadi, Ayman O S

AU - Klotz, Lars Oliver

PY - 2014

Y1 - 2014

N2 - Epidemiological studies have indicated a relationship between the prevalence of diabetes and exposure to arsenic. Mechanisms by which arsenic may cause this diabetogenic effect are largely unknown. The phosphoinositide 3′-kinase (PI3K)/Akt signaling pathway plays an important role in insulin signaling by controlling glucose metabolism, in part through regulating the activity of FoxO transcription factors. The present study aimed at investigating the effect of short and long-term exposure to arsenite on insulin signaling in HepG2 human hepatoma cells, the role of PI3K/Akt signaling therein and the modulation of target genes controlled by insulin. Exposure of cells to arsenite for 24 h rendered cells less responsive toward stimulation of Akt by insulin. At the same time, short-term exposure to arsenite induced a concentration- dependent increase in phosphorylation of Akt at Ser-473, followed by phosphorylation of FoxO proteins at sites known to be phosphorylated by Akt. Phosphorylation of FoxOs was prevented by wortmannin, pointing to the involvement of PI3K. Arsenite exposure resulted in attenuation of FoxO DNA binding and in nuclear exclusion of FoxO1a-EGFP. A 24-h exposure of HepG2 cells to submicromolar concentrations of arsenite resulted in downregulation of glucose 6-phosphatase (G6Pase) and selenoprotein P (SelP) mRNA levels. Curiously, arsenite had a dual effect on SelP protein levels, inducing a small increase in the nanomolar and a distinct decrease in the micromolar concentration range. Interestingly, arsenite-induced long-term effects on G6Pase and SelP mRNA or SelP protein levels were not blocked by the PI3K inhibitor, wortmannin. In conclusion, arsenite perturbs cellular signaling pathways involved in fuel metabolism: it impairs cellular responsiveness toward insulin, while at the same time stimulating insulin-like signaling to attenuate the expression of genes involved in glucose metabolism and the release of the hepatokine SelP, which is known to modulate peripheral insulin sensitivity.

AB - Epidemiological studies have indicated a relationship between the prevalence of diabetes and exposure to arsenic. Mechanisms by which arsenic may cause this diabetogenic effect are largely unknown. The phosphoinositide 3′-kinase (PI3K)/Akt signaling pathway plays an important role in insulin signaling by controlling glucose metabolism, in part through regulating the activity of FoxO transcription factors. The present study aimed at investigating the effect of short and long-term exposure to arsenite on insulin signaling in HepG2 human hepatoma cells, the role of PI3K/Akt signaling therein and the modulation of target genes controlled by insulin. Exposure of cells to arsenite for 24 h rendered cells less responsive toward stimulation of Akt by insulin. At the same time, short-term exposure to arsenite induced a concentration- dependent increase in phosphorylation of Akt at Ser-473, followed by phosphorylation of FoxO proteins at sites known to be phosphorylated by Akt. Phosphorylation of FoxOs was prevented by wortmannin, pointing to the involvement of PI3K. Arsenite exposure resulted in attenuation of FoxO DNA binding and in nuclear exclusion of FoxO1a-EGFP. A 24-h exposure of HepG2 cells to submicromolar concentrations of arsenite resulted in downregulation of glucose 6-phosphatase (G6Pase) and selenoprotein P (SelP) mRNA levels. Curiously, arsenite had a dual effect on SelP protein levels, inducing a small increase in the nanomolar and a distinct decrease in the micromolar concentration range. Interestingly, arsenite-induced long-term effects on G6Pase and SelP mRNA or SelP protein levels were not blocked by the PI3K inhibitor, wortmannin. In conclusion, arsenite perturbs cellular signaling pathways involved in fuel metabolism: it impairs cellular responsiveness toward insulin, while at the same time stimulating insulin-like signaling to attenuate the expression of genes involved in glucose metabolism and the release of the hepatokine SelP, which is known to modulate peripheral insulin sensitivity.

KW - Akt

KW - Arsenic

KW - FoxO transcription factors

KW - HepG2 cells

KW - Insulin signaling

KW - Selenium homeostasis

UR - http://www.scopus.com/inward/record.url?scp=84896317760&partnerID=8YFLogxK

U2 - 10.1007/s10534-014-9714-y

DO - 10.1007/s10534-014-9714-y

M3 - Article

VL - 27

SP - 317

EP - 332

JO - Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine

JF - Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine

SN - 0966-0844

IS - 2

ER -