Steroidogenic control of liver metabolism through a nuclear receptor-network

Alexandra Milona; Vittoria Massafra; Harmjan Vos; Jyoti Naik; Natalia Artigas; Helen A.B. Paterson; Ingrid T.G.W. Bijsmans; Ellen C.L. Willemsen; Jose M. Ramos Pittol; Irene Miguel-Aliaga; Piter Bosma; Boudewijn M.T. Burgering; Catherine Williamson; Santiago Vernia; Waljit S. Dhillo; Saskia W.C. van Mil; Bryn M. Owen

doi:10.1016/j.molmet.2019.09.007

Steroidogenic control of liver metabolism through a nuclear receptor-network

Alexandra Milona
, Vittoria Massafra
, Harmjan Vos
, Jyoti Naik
, Natalia Artigas
, Helen A.B. Paterson
, Ingrid T.G.W. Bijsmans
, Ellen C.L. Willemsen
, Jose M. Ramos Pittol
, Irene Miguel-Aliaga
, Piter Bosma
, Boudewijn M.T. Burgering
, Catherine Williamson
, Santiago Vernia
, Waljit S. Dhillo
, Saskia W.C. van Mil^*
, Bryn M. Owen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown.

METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1.

CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

Original language	English
Pages (from-to)	221-229
Number of pages	9
Journal	Molecular Metabolism
Volume	30
DOIs	https://doi.org/10.1016/j.molmet.2019.09.007 https://doi.org/10.1016/j.molmet.2019.09.007
Publication status	Published - Dec 2019

Keywords

Bile acids
Cyp17a1
Diabetes
Fasting
FGF21
FXR
Gluconeogenesis
Liver
Metabolism
Steroidogenesis

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1-s2.0-S221287781930910XFinal published version, 1.1 MBLicence: CC BY

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Milona, A., Massafra, V., Vos, H., Naik, J., Artigas, N., Paterson, H. A. B., Bijsmans, I. T. G. W., Willemsen, E. C. L., Ramos Pittol, J. M., Miguel-Aliaga, I., Bosma, P., Burgering, B. M. T., Williamson, C., Vernia, S., Dhillo, W. S., van Mil, S. W. C., & Owen, B. M. (2019). Steroidogenic control of liver metabolism through a nuclear receptor-network. Molecular Metabolism, 30, 221-229. https://doi.org/10.1016/j.molmet.2019.09.007, https://doi.org/10.1016/j.molmet.2019.09.007

@article{1012abe3a50342bd96f36148aa581d4d,

title = "Steroidogenic control of liver metabolism through a nuclear receptor-network",

abstract = "OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown.METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1.CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.",

keywords = "Bile acids, Cyp17a1, Diabetes, Fasting, FGF21, FXR, Gluconeogenesis, Liver, Metabolism, Steroidogenesis",

author = "Alexandra Milona and Vittoria Massafra and Harmjan Vos and Jyoti Naik and Natalia Artigas and Paterson, \{Helen A.B.\} and Bijsmans, \{Ingrid T.G.W.\} and Willemsen, \{Ellen C.L.\} and \{Ramos Pittol\}, \{Jose M.\} and Irene Miguel-Aliaga and Piter Bosma and Burgering, \{Boudewijn M.T.\} and Catherine Williamson and Santiago Vernia and Dhillo, \{Waljit S.\} and \{van Mil\}, \{Saskia W.C.\} and Owen, \{Bryn M.\}",

year = "2019",

month = dec,

doi = "10.1016/j.molmet.2019.09.007",

language = "English",

volume = "30",

pages = "221--229",

journal = "Molecular Metabolism",

publisher = "Elsevier",

}

Milona, A, Massafra, V, Vos, H, Naik, J, Artigas, N, Paterson, HAB, Bijsmans, ITGW, Willemsen, ECL, Ramos Pittol, JM, Miguel-Aliaga, I, Bosma, P, Burgering, BMT, Williamson, C, Vernia, S, Dhillo, WS, van Mil, SWC & Owen, BM 2019, 'Steroidogenic control of liver metabolism through a nuclear receptor-network', Molecular Metabolism, vol. 30, pp. 221-229. https://doi.org/10.1016/j.molmet.2019.09.007, https://doi.org/10.1016/j.molmet.2019.09.007

TY - JOUR

T1 - Steroidogenic control of liver metabolism through a nuclear receptor-network

AU - Milona, Alexandra

AU - Massafra, Vittoria

AU - Vos, Harmjan

AU - Naik, Jyoti

AU - Artigas, Natalia

AU - Paterson, Helen A.B.

AU - Bijsmans, Ingrid T.G.W.

AU - Willemsen, Ellen C.L.

AU - Ramos Pittol, Jose M.

AU - Miguel-Aliaga, Irene

AU - Bosma, Piter

AU - Burgering, Boudewijn M.T.

AU - Williamson, Catherine

AU - Vernia, Santiago

AU - Dhillo, Waljit S.

AU - van Mil, Saskia W.C.

AU - Owen, Bryn M.

PY - 2019/12

Y1 - 2019/12

N2 - OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown.METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1.CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

AB - OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown.METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1.CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

KW - Bile acids

KW - Cyp17a1

KW - Diabetes

KW - Fasting

KW - FGF21

KW - FXR

KW - Gluconeogenesis

KW - Liver

KW - Metabolism

KW - Steroidogenesis

UR - https://www.scopus.com/pages/publications/85073732532

U2 - 10.1016/j.molmet.2019.09.007

DO - 10.1016/j.molmet.2019.09.007

M3 - Article

C2 - 31767173

AN - SCOPUS:85073732532

VL - 30

SP - 221

EP - 229

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -

Steroidogenic control of liver metabolism through a nuclear receptor-network

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Keywords

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