CoChat
Sign Up
Cited by 53Adrenal Hormones and DisordersEstrogen and related hormone effectsMetabolism and Genetic Disorders

Molecular regulation of urea cycle function by the liver glucocorticoid receptor

Open access
Okun, Jürgen G., Conway, Sean, Schmidt, Kathrin V., Schumacher, Jonas, Wang, Xiaoyue, de Guia, Roldan, Zota, Annika, Klement, Johanna +5 more·2015·Molecular Metabolism
DOI 10.1016/j.molmet.2015.07.006PMC PMC4588454
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.molmet.2015.07.006

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Elevated arginase expression is associated with increased inflammatory cytokines and GC activity.

    “Furthermore, elevated arginase expression is shown to be associated with increased inflammatory cytokines and GC activity (59), which could further lead to a lower urea cycle flux, reduced arginine levels, and subsequent nitric oxide production (5).”

    From Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity (2019) · cites this paper as [59]

    The Results (page not provided) report that dexamethasone induced liver Arg1 expression and that this effect was blocked by glucocorticoid-receptor loss of function. The cited paper therefore supports the GC-activity part of the claim, but the passages do not link elevated arginase expression to increased inflammatory cytokines. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 52

  1. [1]Overman R.A. Yeh J.Y. Deal C.L. Prevalence of oral glucocorticoid usage in the United States: a general population perspective Arthritis Care & Research (Hoboken) 65 2 2013 294 298 22807233
  2. [2]Rose A.J. Vegiopoulos A. Herzig S. Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations The Journal of Steroid Biochemistry and Molecular Biology 122 1–3 2010 10 20 20170729
  3. [4]Magomedova L. Cummins C.L. Glucocorticoids and metabolic control Handbook of Experimental Pharmacology 2015 25917083
  4. [5]Schimmer B.P. Parker K.L. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones Hardman J.G. Limbird L.E. The pharmacological basis of therapeutics 9th ed 1996 McGraw-Hill New York 1459 1485
  5. [6]Opherk C. Tronche F. Kellendonk C. Kohlmüller D. Schulze A. Schmid W. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus Molecular Endocrinology 18 6 2004 1346 1353 15031319
  6. [7]Reichardt S.D. Foller M. Rexhepaj R. Pathare G. Minnich K. Tuckermann J.P. Glucocorticoids enhance intestinal glucose uptake via the dimerized glucocorticoid receptor in enterocytes Endocrinology 153 4 2012 1783 1794 22294744
  7. [8]Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1 Nature 413 6852 2001 179 183 11557984
  8. [9]de Guia R.M. Rose A.J. Sommerfeld A. Seibert O. Strzoda D. Zota A. microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis The EMBO Journal 34 3 2015 344 360 25510864 PMC4339121
  9. [10]Lemke U. Krones-Herzig A. Berriel Diaz M. Narvekar P. Ziegler A. Vegiopoulos A. The glucocorticoid receptor controls hepatic dyslipidemia through Hes1 Cell Metabolism 8 3 2008 212 223 18762022
  10. [11]Watson M.L. Baehr L.M. Reichardt H.M. Tuckermann J.P. Bodine S.C. Furlow J.D. A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure American Journal of Physiology. Endocrinology and Metabolism 302 10 2012 E1210 E1220 22354783 PMC3361985
  11. [12]Hu Z. Wang H. Lee I.H. Du J. Mitch W.E. Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice The Journal of Clinical Investigation 119 10 2009 3059 3069 19759515 PMC2752071
  12. [13]Rose A.J. Berriel Diaz M. Reimann A. Klement J. Walcher T. Krones-Herzig A. Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor Cell Metabolism 14 1 2011 123 130 21723510
  13. [14]Rauch A. Seitz S. Baschant U. Schilling A.F. Illing A. Stride B. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor Cell Metabolism 11 6 2010 517 531 20519123
  14. [15]de Kloet A.D. Krause E.G. Solomon M.B. Flak J.N. Scott K.A. Kim D.H. Adipocyte glucocorticoid receptors mediate fat-to-brain signaling Psychoneuroendocrinology 56 2015 110 119 25808702 PMC4511277
  15. [16]Shimizu N. Maruyama T. Yoshikawa N. Matsumiya R. Ma Y. Ito N. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling Nature Communications 6 2015 6693 PMC4396397 25827749
  16. [17]Kellendonk C. Eiden S. Kretz O. Schutz G. Schmidt I. Tronche F. Inactivation of the GR in the nervous system affects energy accumulation Endocrinology 143 6 2002 2333 2340 12021198
  17. [18]Klement J. Hubold C. Cords H. Oltmanns K.M. Hallschmid M. Born J. High-calorie glucose-rich food attenuates neuroglycopenic symptoms in patients with Addison's disease The Journal of Cinical Endocrinology and Metabolism 95 2 2010 522 528 19965917
  18. [20]Tronche F. Opherk C. Moriggl R. Kellendonk C. Reimann A. Schwake L. Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth Genes & Development 18 5 2004 492 497 15037546 PMC374231
  19. [21]Gray S. Wang B. Orihuela Y. Hong E.G. Fisch S. Haldar S. Regulation of gluconeogenesis by Kruppel-like factor 15 Cell Metabolism 5 4 2007 305 312 17403374 PMC1892530
  20. [22]Domanskyi A. Alter H. Vogt M.A. Gass P. Vinnikov I.A. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance Frontiers in Cellular Neuroscience 8 2014 275 25249938 PMC4158790
  21. [23]de Graaf I.A. Olinga P. de Jager M.H. Merema M.T. de Kanter R. van de Kerkhof E.G. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies Nature Protocols 5 9 2010 1540 1551 20725069
  22. [24]Patti M.E. Brambilla E. Luzi L. Landaker E.J. Kahn C.R. Bidirectional modulation of insulin action by amino acids The Journal of Clinical Investigation 101 7 1998 1519 1529 9525995 PMC508730
  23. [25]Wei L.H. Wu G. Morris S.M. Jr. Ignarro L.J. Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation Proceedings of the National Academy of Sciences of the United States of America 98 16 2001 9260 9264 11470919 PMC55408
  24. [26]Graham T. McIntosh J. Work L.M. Nathwani A. Baker A.H. Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats Genetic Vaccines and Therapy 6 2008 9 18312698 PMC2267784
  25. [27]Sauer S.W. Okun J.G. Fricker G. Mahringer A. Muller I. Crnic L.R. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency Journal of Neurochemistry 97 3 2006 899 910 16573641
  26. [28]Rose A.J. Alsted T.J. Kobbero J.B. Richter E.A. Regulation and function of Ca2+-calmodulin-dependent protein kinase II of fast-twitch rat skeletal muscle The Journal of Physiology 580 Pt.3 2007 993 1005 17272343 PMC2075445
  27. [29]Grontved L. John S. Baek S. Liu Y. Buckley J.R. Vinson C. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements The EMBO Journal 32 11 2013 1568 1583 23665916 PMC3671252
  28. [30]Langmead B. Aligning short sequencing reads with bowtie. Curr protoc bioinformatics 2010 [Chapter 11]: p. Unit 11 7 PMC3010897 21154709
  29. [31]Zhang Y. Liu T. Meyer C.A. Eeckhoute J. Johnson D.S. Bernstein B.E. Model-based analysis of ChIP-Seq (MACS) Genome Biology 9 9 2008 R137 18798982 PMC2592715
  30. [32]Robinson J.T. Thorvaldsdottir H. Winckler W. Guttman M. Lander E.S. Getz G. Integrative genomics viewer Nature Biotechnology 29 1 2011 24 26 PMC3346182 21221095
  31. [33]Meijer A.J. Lamers W.H. Chamuleau R.A. Nitrogen metabolism and ornithine cycle function Physiological Reviews 70 3 1990 701 748 2194222
  32. [34]Gropman A.L. Summar M. Leonard J.V. Neurological implications of urea cycle disorders Journal of Inherited Metabolic Disease 30 6 2007 865 879 18038189 PMC3758693
  33. [35]Lim H.W. Uhlenhaut N.H. Rauch A. Weiner J. Hubner S. Hubner N. Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo Genome Research 25 6 2015 836 844 25957148 PMC4448680
  34. [36]Jantzen H.M. Strahle U. Gloss B. Stewart F. Schmid W. Boshart M. Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene Cell 49 1 1987 29 38 2881624
  35. [37]Sigsgaard I. Almdal T. Hansen B.A. Vilstrup H. Dexamethasone increases the capacity of urea synthesis time dependently and reduces the body weight of rats Liver 8 4 1988 193 197 3047515
  36. [38]Grofte T. Jensen D.S. Gronbaek H. Wolthers T. Jensen S.A. Tygstrup N. Effects of growth hormone on steroid-induced increase in ability of urea synthesis and urea enzyme mRNA levels American Journal of Physiology 275 1 Pt 1 1998 E79 E86 9688877
  37. [39]Wolthers T. Hamberg O. Grofte T. Vilstrup H. Effects of budesonide and prednisolone on hepatic kinetics for urea synthesis Journal of Hepatology 33 4 2000 549 554 11059859
  38. [40]Heindorff H. Almdal T.P. Vilstrup H. Blockade of glucocorticoid receptors prevents the increase in urea synthesis after hysterectomy in rats European Journal of Clinical Investigation 21 6 1991 625 630 1778224
  39. [41]Heindorff H.A. The hepatic catabolic stress response. Hormonal regulation of urea synthesis after surgery Danish Medical Bulletin 40 2 1993 224 234 8495598
  40. [42]Caparroz-Assef S.M. Bersani-Amado C.A. Kelmer-Bracht A.M. Bracht A. Ishii-Iwamoto E.L. The metabolic changes caused by dexamethasone in the adjuvant-induced arthritic rat Molecular and Cellular Biochemistry 302 1–2 2007 87 98 17347874
  41. [43]Iyer R.K. Yoo P.K. Kern R.M. Rozengurt N. Tsoa R. O'Brien W.E. Mouse model for human arginase deficiency Molecular and Cellular Biology 22 13 2002 4491 4498 12052859 PMC133904
  42. [44]Kasten J. Hu C. Bhargava R. Park H. Tai D. Byrne J.A. Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse Molecular Genetics and Metabolism 110 3 2013 222 230 23920045 PMC3800271
  43. [45]Lee E.K. Hu C. Bhargava R. Rozengurt N. Stout D. Grody W.W. Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy Molecular Therapy: The Journal of the American Society of Gene Therapy 20 10 2012 1844 1851 22760543 PMC3464644
  44. [46]Ulbright C. Snodgrass P.J. Coordinate induction of the urea cycle enzymes by glucagon and dexamethasone is accomplished by three different mechanisms Archives of Biochemistry and Biophysics 301 2 1993 237 243 8460937
  45. [47]Gotoh T. Chowdhury S. Takiguchi M. Mori M. The glucocorticoid-responsive gene cascade. Activation of the rat arginase gene through induction of C/EBPbeta The Journal of Biological Chemistry 272 6 1997 3694 3698 9013625
  46. [48]Kimura T. Chowdhury S. Tanaka T. Shimizu A. Iwase K. Oyadomari S. CCAAT/enhancer-binding protein beta is required for activation of genes for ornithine cycle enzymes by glucocorticoids and glucagon in primary-cultured hepatocytes FEBS Letters 494 1–2 2001 105 111 11297744
  47. [49]Phuc Le P. Friedman J.R. Schug J. Brestelli J.E. Parker J.B. Bochkis I.M. Glucocorticoid receptor-dependent gene regulatory networks PLoS Genetics 1 2 2005 e16 16110340 PMC1186734
  48. [50]Miranda T.B. Morris S.A. Hager G.L. Complex genomic interactions in the dynamic regulation of transcription by the glucocorticoid receptor Molecular and Cellular Endocrinology 380 1–2 2013 16 24 23499945 PMC3724757
  49. [51]Tannour-Louet M. York B. Tang K. Stashi E. Bouguerra H. Zhou S. Hepatic SRC-1 activity orchestrates transcriptional circuitries of amino acid pathways with potential relevance for human metabolic pathogenesis Molecular Endocrinology 28 10 2014 1707 1718 25148457 PMC4179626
  50. [52]Swali A. Walker E.A. Lavery G.G. Tomlinson J.W. Stewart P.M. 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets Diabetologia 51 11 2008 2003 2011 18779947
  51. [53]Wise J.K. Hendler R. Felig P. Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man The Journal of Clinical Investigation 52 11 1973 2774 2782 4748510 PMC302545
  52. [54]Magnusson I. Rothman D.L. Katz L.D. Shulman R.G. Shulman G.I. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study The Journal of Clinical Investigation 90 4 1992 1323 1327 1401068 PMC443176

Cited by

Sorted by citations

Authors
Okun, J. G., Conway, S., Schmidt, K. V., Schumacher, J., Wang, X., de Guia, R., Zota, A., Klement, J., Seibert, O., Peters, A., Maida, A., Herzig, S., & Rose, A. J.
Affiliations
  • Heidelberg University (DE)
  • German Cancer Research Center (DE)
  • University of Lübeck (DE)
Corresponding author
Rose, Adam J.
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2015-10
Volume
4
Issue
10
Pages
732-740
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2015.07.006
PMC
PMC4588454
OpenAlex
W2118035126
Cited by
53
References
3
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 6 · 2017: 3 · 2016: 3
FWCI
3.48
Type
journal article
Language
en
Update notices
erratum (2020-11-01)
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Site cant be reached (submittedVersion, cc-by-nc-nd)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
glucocorticoid receptor, urea cycle, arginase-1, hyperammonemia, glucocorticoid adverse effects, amino acid metabolism, acylcarnitines, Addison's disease, dexamethasone, neuromuscular dysfunction, transcriptional regulation, urea synthesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review