Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes

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.

mtDNA depletion‐like syndrome in Wilson disease

“…Thirty-seven healthy controls and 61 patients with a diagnosis of WD according to Leipzig criteria were previously described in detail [25][26][27] and included in the metabolomic study; of these, 47 WD were included in the mtDNA study ( Figure S3; Table S3). Informed written consent was obtained from all subjects and patients, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Review Board at the University of California, Davis.…”

Lipid and energy metabolism in Wilson disease

“… 98 Relevant to VLDL metabolism, we and others have described a dysregulated methionine cycle and altered choline levels in humans and animal models of WD. 77 , 99 – 101 These dysregulations in methionine and choline metabolism may impact the assembly or export of VLDL in WD. Methionine is a precursor to S-adenosylmethionine (SAM), a universal methyl-group donor, which is required for transmethylation reactions.…”

“… 107 We recently reported a dysregulated serum phospholipid profile in WD patients with profound alterations in PC levels compared to healthy controls as well as a down-regulation of PC synthesis genes in tx-j mice, including Pemt , [phosphate cytidylyltransferase 1 choline-alpha], and choline phosphotransferase 1. 101 In general, alterations in phospholipids are implicated in hepatic steatosis, 108 – 111 and evidence indicates both pathways, hepatic PC synthesis via CDP-choline or PEMT, are critical for VLDL production. 104 , 112 …”

Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation

“…The growing knowledge about WD pathogenesis has also contributed to the understanding of more common conditions, including alcohol-associated liver disease, nonalcoholic fatty liver, and autoimmune hepatitis (1)(2)(3), as the involved pathogenic pathways partially overlap and the clinical and laboratory presentations have common features (4)(5)(6). Although the genetic deficiency in WD causes copper accumulation, gene variants themselves do not explain the whole array of clinical manifestations as there is no evidence of genotypephenotype correlation (7). Given the similarity of systemic involvement and hepatic phenotypes with other metabolic liver diseases, WD is ideal for understanding the mechanisms leading to epigenetic and metabolic dysregulation during disease onset and progression as well as the extent of organ involvement.…”