Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

Research output: Contribution to journalArticlepeer-review

Standard

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo. / Nikolaou, Nikolaos; Arvaniti, Anastasia; Appanna, Nathan; Sharp, Anna; Hughes, Beverly A; Digweed, Dena; Whitaker, Martin J; Ross, Richard; Arlt, Wiebke; Penning, Trevor M; Morris, Karen; George, Sherly; Keevil, Brian G; Hodson, Leanne; Gathercole, Laura L; Tomlinson, Jeremy W.

In: Journal of Endocrinology, Vol. 245, No. 2, 05.2020, p. 207–218.

Research output: Contribution to journalArticlepeer-review

Harvard

Nikolaou, N, Arvaniti, A, Appanna, N, Sharp, A, Hughes, BA, Digweed, D, Whitaker, MJ, Ross, R, Arlt, W, Penning, TM, Morris, K, George, S, Keevil, BG, Hodson, L, Gathercole, LL & Tomlinson, JW 2020, 'Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo', Journal of Endocrinology, vol. 245, no. 2, pp. 207–218. https://doi.org/10.1530/JOE-19-0473

APA

Nikolaou, N., Arvaniti, A., Appanna, N., Sharp, A., Hughes, B. A., Digweed, D., Whitaker, M. J., Ross, R., Arlt, W., Penning, T. M., Morris, K., George, S., Keevil, B. G., Hodson, L., Gathercole, L. L., & Tomlinson, J. W. (2020). Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo. Journal of Endocrinology, 245(2), 207–218. https://doi.org/10.1530/JOE-19-0473

Vancouver

Nikolaou N, Arvaniti A, Appanna N, Sharp A, Hughes BA, Digweed D et al. Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo. Journal of Endocrinology. 2020 May;245(2):207–218. https://doi.org/10.1530/JOE-19-0473

Author

Nikolaou, Nikolaos ; Arvaniti, Anastasia ; Appanna, Nathan ; Sharp, Anna ; Hughes, Beverly A ; Digweed, Dena ; Whitaker, Martin J ; Ross, Richard ; Arlt, Wiebke ; Penning, Trevor M ; Morris, Karen ; George, Sherly ; Keevil, Brian G ; Hodson, Leanne ; Gathercole, Laura L ; Tomlinson, Jeremy W. / Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo. In: Journal of Endocrinology. 2020 ; Vol. 245, No. 2. pp. 207–218.

Bibtex

@article{9bb9192887ba4377866dc2cc00135bde,
title = "Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo",
abstract = "Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.",
keywords = "5β-reductase, NAFLD, gluconeogenesis, dexamethasone, glycogen, liver",
author = "Nikolaos Nikolaou and Anastasia Arvaniti and Nathan Appanna and Anna Sharp and Hughes, {Beverly A} and Dena Digweed and Whitaker, {Martin J} and Richard Ross and Wiebke Arlt and Penning, {Trevor M} and Karen Morris and Sherly George and Keevil, {Brian G} and Leanne Hodson and Gathercole, {Laura L} and Tomlinson, {Jeremy W}",
year = "2020",
month = may,
doi = "10.1530/JOE-19-0473",
language = "English",
volume = "245",
pages = "207–218",
journal = "Journal of Endocrinology",
issn = "0022-0795",
publisher = "BioScientifica",
number = "2",

}

RIS

TY - JOUR

T1 - Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

AU - Nikolaou, Nikolaos

AU - Arvaniti, Anastasia

AU - Appanna, Nathan

AU - Sharp, Anna

AU - Hughes, Beverly A

AU - Digweed, Dena

AU - Whitaker, Martin J

AU - Ross, Richard

AU - Arlt, Wiebke

AU - Penning, Trevor M

AU - Morris, Karen

AU - George, Sherly

AU - Keevil, Brian G

AU - Hodson, Leanne

AU - Gathercole, Laura L

AU - Tomlinson, Jeremy W

PY - 2020/5

Y1 - 2020/5

N2 - Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.

AB - Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.

KW - 5β-reductase

KW - NAFLD

KW - gluconeogenesis

KW - dexamethasone

KW - glycogen

KW - liver

U2 - 10.1530/JOE-19-0473

DO - 10.1530/JOE-19-0473

M3 - Article

VL - 245

SP - 207

EP - 218

JO - Journal of Endocrinology

JF - Journal of Endocrinology

SN - 0022-0795

IS - 2

ER -