Dataset Information

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.

SUBMITTER: Mazi TA

PROVIDER: S-EPMC6928853 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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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 TA Sarode Gaurav V GV Czlonkowska Anna A Litwin Tomasz T Kim Kyoungmi K Shibata Noreene M NM Medici Valentina V

International journal of molecular sciences 20191126 23

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, aroma ...[more]

PMID: 31779102

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Project description:Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered. Among individual genes, only HMG-CoA reductase (Hmgcr) was hypermethylated, and no methylation changes were observed in fatty acid synthase (Fasn), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (Nfκb1), c-Jun, B-cell lymphoma 2 (Bcl-2) and Caspase 3. NAFLD was associated with hepatic methionine deficiency and homocysteine elevation, resulting mainly from impaired homocysteine remethylation, and aberrancy in methyltransferase reactions. Despite increased PRMT1 expression, hepatic ADMA was depleted while circulating ADMA was increased, suggesting increased export to circulation.

Project description:BackgroundEmerging data support a role for lipids in non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in humans. With experimental models such data can be challenged or validated. Mice fed a low-methionine, choline-deficient (LMCD) diet develop NASH and, when injected with diethylnitrosamine (DEN), HCC. Here, lipidomic analysis was used to elucidate whether the NASH and HCC associated lipid derangements resemble the lipid profile of the human disease.MethodsLipids were measured in the liver of mice fed a control or a LMCD diet for 16 weeks. DEN was injected at young age to initiate hepatocarcinogenesis. DEN treatment associated changes of the lipid composition and the tumor lipidome were evaluated.ResultsLMCD diet fed mice accumulated ceramides and triacylglycerols in the liver. Phospholipids enriched with monounsaturated fatty acids were also increased, whereas hepatic cholesterol levels remained unchanged in the LMCD model. Phosphatidylcholine and lysophosphatidylcholine concentrations declined in the liver of LMCD diet fed mice. The changes of most lipids associated with LMCD diet feeding were similar between water and DEN injected mice. Several polyunsaturated (PU) diacylglycerol species were already low in the liver of DEN injected mice fed the control diet. Tumors developed in the liver of LMCD diet fed mice injected with DEN. The tumor specific lipid profile, however, did not resemble the decrease of ceramides and PU phospholipids, which was consistently described in human HCC. Triacylglycerols declined in the cancer tissues, which is in accordance with a low expression of lipogenic enzymes in the tumors.ConclusionsThe LMCD model is suitable to study NASH associated lipid reprogramming. Hepatic lipid profile was modestly modified in the DEN injected mice suggesting a function of these derangements in carcinogenesis. Lipid composition of liver tumors did not resemble the human HCC lipidome, and most notably, lipogenesis and triacylglycerol levels were suppressed.

Dataset Information

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

Publications

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

Similar Datasets

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