Molecular regulation of urea cycle function by the liver glucocorticoid receptor.
OBJECTIVE
One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function.


METHODS
Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices.


RESULTS
A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (∼+32%) and loss (∼-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR.


CONCLUSIONS
The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.
Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany.
Jürgen G
JG
Okun
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
Sean
S
Conway
Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany.
Kathrin V
KV
Schmidt
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
Jonas
J
Schumacher
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
Xiaoyue
X
Wang
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
Roldan
R
de Guia
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany ; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, 85764 Neuherberg, Germany.
Annika
A
Zota
Department of Internal Medicine, University of Lübeck, 23538 Lübeck, Germany.
Johanna
J
Klement
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
Oksana
O
Seibert
Department of Internal Medicine, University of Lübeck, 23538 Lübeck, Germany.
Achim
A
Peters
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany ; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, 85764 Neuherberg, Germany.
Adriano
A
Maida
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany ; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, 85764 Neuherberg, Germany.
Stephan
S
Herzig
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
Adam J
AJ
Rose
Amino acid; Metabolism; Protein; Stress