Abstract
Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation.
| Original language | English (US) |
|---|---|
| Article number | 5937 |
| Journal | International journal of molecular sciences |
| Volume | 20 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2019 |
Fingerprint
Keywords
- Choline
- Copper
- Histidine
- Metabolomics
- Neurotransmitters
- Phenylalanine
- Phospholipids
- Steatosis
- Tyrosine
ASJC Scopus subject areas
- Catalysis
- Molecular Biology
- Spectroscopy
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry
Cite this
Dysregulated choline, methionine, and aromatic amino acid metabolism in patients with wilson disease : Exploratory metabolomic profiling and implications for hepatic and neurologic phenotypes. / Mazi, Tagreed A.; Sarode, Gaurav V.; Czlonkowska, Anna; Litwin, Tomasz; Kim, Kyoungmi; Shibata, Noreene M.; Medici, Valentina.
In: International journal of molecular sciences, Vol. 20, No. 23, 5937, 01.12.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dysregulated choline, methionine, and aromatic amino acid metabolism in patients with wilson disease
T2 - Exploratory metabolomic profiling and implications for hepatic and neurologic phenotypes
AU - Mazi, Tagreed A.
AU - Sarode, Gaurav V.
AU - Czlonkowska, Anna
AU - Litwin, Tomasz
AU - Kim, Kyoungmi
AU - Shibata, Noreene M.
AU - Medici, Valentina
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation.
AB - Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation.
KW - Choline
KW - Copper
KW - Histidine
KW - Metabolomics
KW - Neurotransmitters
KW - Phenylalanine
KW - Phospholipids
KW - Steatosis
KW - Tyrosine
UR - http://www.scopus.com/inward/record.url?scp=85075594296&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075594296&partnerID=8YFLogxK
U2 - 10.3390/ijms20235937
DO - 10.3390/ijms20235937
M3 - Article
C2 - 31779102
AN - SCOPUS:85075594296
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 23
M1 - 5937
ER -