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September 1990 - present
Publications
Publications (433)
Dietary choline is needed to maintain normal health, including normal liver function in adults. Fatty liver induced by a choline-deficient diet has been consistently observed in human and animal studies. The effect of insufficient choline intake on hepatic fat accumulation is specific and reversible when choline is added to the diet. Choline requir...
Objective
Fetal alcohol spectrum disorder (FASD) is a life-long condition, and few interventions have been developed to improve the neurodevelopmental course in this population. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one...
Choline availability regulates neural progenitor cell proliferation and differentiation in the developing cerebral cortex. Here, we investigated the molecular mechanism underlying this process and demonstrated that choline regulates the transcription factor SOX4 in neural progenitor cells. Specifically, we found that low choline intake during neuro...
Background
Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age durin...
Background
The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function.
Objective
Choline supplements confer cognitive improvement for those diagnosed with fetal...
Background:
Choline deficiency has numerous negative health consequences; although the preponderance of the US population consumes less than the recommended Adequate Intake (AI), clinical assessment of choline status is difficult. Further, several pathways involved in primary metabolism of choline are estrogen-sensitive and the AI for premenopausa...
Objective:
To examine the association between dietary intake of choline and betaine with the risk of type 2 diabetes.
Research design and methods:
Among 13,440 Atherosclerosis Risk in Communities (ARIC) study participants, the prospective longitudinal association between dietary choline and betaine intake and the risk of type 2 diabetes was asse...
Background:
Despite the high prevalence of fetal alcohol spectrum disorder (FASD), there are few interventions targeting its core neurocognitive and behavioral deficits. FASD is often conceptualized as static and permanent, but interventions that capitalize on brain plasticity and critical developmental windows are emerging. We present a long-term...
Choline is an essential nutrient important for metabolism and numerous biological functions. Dietary requirements for choline are highly individualized and are based on several factors including genetics and gender; this nutrigenetic approach serves as an example of a new way of thinking about heterogeneity in individuals' nutritional requirements...
Choline is an essential nutrient for proper liver, muscle, and brain functions as well as for lipid metabolism and cellular membrane composition and repair. Humans can produce small amounts of choline via the hepatic phosphatidylethanolamine N-methyltransferase pathway; however, most individuals must consume this vitamin through the diet to prevent...
Adequate supply of choline, an essential nutrient, is necessary to support proper brain development. Whether prenatal choline availability plays a role in development of the visual system is currently unknown. In this study, we addressed the role of in utero choline supply for the development and later function of the retina in a mouse model. We lo...
Purpose
Two prior cohort studies suggested that choline, but not betaine intake, is associated with an increased risk of advanced prostate cancer (PCa). Given that evidence remains limited, we evaluated whether intakes of choline and derivative betaine are associated with total and lethal PCa risk and PCa death in men with PCa.
Methods
We included...
Nutrients and food-derived bioactive molecules must transit complex metabolic pathways, and these pathways vary between people. Metabolic heterogeneity is caused by genetic variation, epigenetic variation, differences in microbiome composition and function, lifestyle differences and by variation in environmental exposures. This review discusses a n...
Choline availability modulates neurogenesis and cerebral cortex development through the regulation of neural progenitor cell (NPC) proliferative and differentiation capacity. In this study, we demonstrated that cortical NPC self‐renewal is controlled by choline via the expression of a microRNA (miR‐129‐5p), whose role in the developing brain has no...
Many Americans have inadequate intakes of several nutrients, and the Dietary Guidelines for Americans 2015-2020 identified vitamins A, C, D, and E, in addition to calcium, magnesium, iron, potassium, choline, and fiber as "underconsumed nutrients". Based on nationally representative data on 10,698 adults from National Health and Nutrition Examinati...
Many Americans have inadequate intakes of several nutrients. The Dietary Guidelinesfor Americans 2015–2020 specifically identified vitamins A, C, D and E, calcium, magnesium, iron, potassium, choline and fiber as “underconsumed nutrients”. Based on nationally representative data in 10,698 adults from National Health and Nutrition Examination Survey...
Although >50% of U.S. adults use dietary supplements, little information is available on the impact of supplement use frequency on nutrient intakes and deficiencies. Based on nationally representative data in 10,698 adults from the National Health and Nutrition Examination Surveys (NHANES) 2009 to 2012, assessments were made of intakes from food al...
Using a mouse model, this study examined the impact of lack of betaine homocysteine S-methyltransferase (BHMT) on neurological function. Bhmt−/− mice maintained on a control diet had elevated concentrations of homocysteine, reduced total brain magnetic resonance imaging (MRI) volume, as well as impaired reference and short-term memories. The result...
During and after missions on the International Space Station, some astronauts experience ophthalmic changes, including choroidal folds, optic disc edema, cotton-wool spots, globe flattening, and refraction changes. Astronauts with ophthalmic issues had significantly higher plasma concentrations of metabolites that are associated with the 1-carbon m...
The MTHFD1 gene encodes for methylenetetrahydrofolate dehydrogenase 1, an enzyme that has an important role in folate-mediated one-carbon metabolism. In people, a single nucleotide polymorphism of this gene (1958G > A; rs2236225) is associated with increased risk for bipolar disorder and schizophrenia, neural tube and other birth defects. Mice homo...
Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations of S-adenosylhomocysteine and S-adenosylmethionine. Some of the epigenetic mechanisms...
Background: There is a potential role of choline in cardiovascular and cerebrovascular disease through its involvement in lipid and one-carbon metabolism.
Objective: We evaluated the associations of plasma choline and choline-related compounds with cardiometabolic risk factors, history of cardiovascular disease, and cerebrovascular pathology.
Desig...
Although many studies have been conducted on the components present in human breast milk (HM), research on the differences of chemical metabolites between HM, bovine milk (BM) and formula milk (FM) is limited. This study was to explore the chemical diversity of HM, BM and FM by metabolomic approaches. GC-TOFMS and UPLC-QTOFMS were applied to invest...
Folate-B12-dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway (catalyzed by betaine-homocysteine methyltransferase; BHMT) for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J Bhmt-null mice at 4, 12, 24...
Background
Clinical studies implicate trimethylamine N‐oxide (TMAO; a gut microbiota‐dependent nutrient metabolite) in cardiovascular disease risk. There is a lack of population‐based data on the role of TMAO in advancing early atherosclerotic disease. We tested the prospective associations between TMAO and coronary artery calcium (CAC) and carotid...
This supplement examines the role of vitamin and mineral supplements in increasing nutrient intake and reducing nutrient deficiencies and inadequacies. Although research is needed to study the effects of dietary supplements on chronic disease outcomes, US health care providers need to know how to advise their patients about adding vitamins and mine...
Choline is an essential nutrient that is obtained from the diet and through de novo synthesis. During fetal development, the embryo's source of choline is obtained form its mother. Our group demonstrated in mice that maternal choline deficiency (CD) during embryo development changes the proliferation rates and differentiation patterns of neural pro...
Maternal alcohol consumption during pregnancy leads to a range of long lasting developmental defects and deficits in the child that include effects on brain and behavior, collectively known as Fetal Alcohol Spectrum Disorders (FASD). The neurobiology is complex, not well understood and there is no effective treatment. A recent study reported benefi...
Anti‐oxidants in foods are traditionally thought to act by trapping free radicals thereby preventing cellular damage to organelles, membranes and DNA. However the structures and properties of many of these molecules suggest they are poor free radical scavengers and may even function as weak pro‐oxidants (electrophiles) that can activate the NRF2/an...
Choline, an essential nutrient, regulates brain development through its role in maintaining the pool of neural progenitor cells. The role of choline in the development of the retina, however, is unknown. In this study, we modulated choline intake in mice during pregnancy and assessed the effects of low choline (LC) diet on the development and funct...
Objective: Trimethylamine N-oxide (TMAO), a gut microbiota-dependent nutrient metabolite, has been implicated in the development of cardiovascular disease (CVD). TMAO is excreted in the urine and high levels may reflect poor kidney function, an independent risk factor for CVD. We tested the association between TMAO and coronary artery calcium (CAC)...
Academic achievement in adolescents is correlated with 1-carbon metabolism (1-CM), as folate intake is positively related and total plasma homocysteine (tHcy) negatively related to academic success. Because another 1-CM nutrient, choline is essential for fetal neurocognitive development, we hypothesized that choline and betaine could also be positi...
Maternal diets low in choline, an essential nutrient, increase the risk of neural tube defects and lead to low performance on cognitive tests in children. However, the consequences of maternal dietary choline deficiency for the development and structural organization of the cerebral cortex remain unknown. In this study, we fed mouse dams either con...
Background:
Fetal alcohol spectrum disorders (FASDs) are conditions characterized by physical anomalies, neurodevelopmental abnormalities, and neurocognitive deficits, including intellectual, executive, and memory deficits. There are no specific biological treatments for FASDs, but rodent models have shown that prenatal or postnatal choline supple...
Ophthalmic changes have occurred in a subset of astronauts on International Space Station missions. Visual deterioration is considered the greatest human health risk of space flight. Affected astronauts exhibit higher concentrations of 1-carbon metabolites (e.g., homocysteine) before flight. We hypothesized that genetic variations in 1-carbon metab...
The biological effects of antioxidant nutrients are mediated in part by activation of antioxidant response elements (AREs) on genes for enzymes involved in endogenous pathways that prevent free radical damage. Traditional approaches for identifying antioxidant molecules in foods, such as total phenolic compound (TP) content or oxygen radical absorp...
There is a growing interest in analyzing choline, betaine and their gut microbial metabolites including trimethylamine (TMA) and trimethylamine N-oxide (TMAO) in body fluids due to the high relevance of these compounds for human health and diseases. A stable isotope dilution (SID)-LC-MRM/MS assay was developed for the simultaneous determination of...
Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary...
Intermediates of the one‐carbon metabolic pathway are altered in astronauts who experience vision‐related issues during and after space flight. Serum concentrations of homocysteine, cystathionine, 2‐methylcitric acid, and methylmalonic acid were higher in astronauts with ophthalmic changes than in those without (Zwart et al., J Nutr , 142:427‐31, 2...
Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice.
We studied mice with disruptions in Nr0b2 (called SHP-null mice) Bhmt, or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls)...
Fibroblasts from a patient with postural orthostatic tachycardia syndrome (POTS), who presented with low plasma choline and betaine, were studied to determine the metabolic characteristics of the choline deficiency. Choline is required for the synthesis of the phospholipid phosphatidylcholine (PC) and for betaine, an important osmoregulator. Here,...
Background:
It is important to understand whether eating eggs, which are a major source of dietary choline, results in increased exposure to trimethylamine-N-oxide (TMAO), which is purported to be a risk factor for developing heart disease.
Objective:
We determined whether humans eating eggs generate TMAO and, if so, whether there is an associat...
In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significan...
Choline is an essential nutrient critical to brain health. Our objective was to evaluate the association of plasma choline (Cho) and Cho‐related compounds with cognition and cerebrovascular pathology (CvP) in a subset of the Nutrition, Aging, and Memory in Elders cohort who had undergone MRI, cognitive testing, and had archived plasma (n=296, mean...
OBJECTIVE: The aim of this study was to explore the relation of human milk lutein, choline, and DHA with recognition memory abilities of 6‐month‐olds.
METHODS: Two hundred breastfeeding dyads were enrolled when the infants were 3‐4 months of age. Milk samples were obtained and analyzed for fatty acids, lutein, and choline. One hundred two of the 20...
Choline deficiency can alter the development of fetal hippocampus. Epidermal growth factor (EGF) is pivotal for neural progenitor cell (NPC) proliferation in the embryonic ventricular and subventricular zones. To address the possibility that EGF signaling pathway plays a functional role in the effect of choline deficiency, we cultured NPCs derived...
We previously identified three functional single nucleotide polymorphisms (SNPs) that modulate sensitivity to dietary choline deficiency‐mediated organ dysfunction: CHDH rs12676, MTHFD1 rs2236225 and PEMT rs12325817. We aimed to broaden our understanding of the contribution of genetic aberrations in the 1‐carbon pathway to choline deficiency sensit...
Science has been revolutionized by the advent of high‐throughput technologies of the ‐omic scale. Nutrigenomics aims to identify genetic and dietary interactions that affect gene expression. A goal of nutrigenomics is to identify novel gene x diet interactions that increase susceptibility to disease. Nutrigenomics approaches can incorporate multipl...
Choline is an essential dietary nutrient and, along with its metabolites, has profound implications in cell signaling, methyl group donation, neurotransmitter synthesis, structural integrity of cell membranes, and fetal neurogenesis. Several important single nucleotide polymorphisms (SNPs) in the choline and folate metabolism pathways have been ass...
Effect alleles (alleles with a polymorphism that is associated with the effect being measured) in a small number of single-nucleotide polymorphisms (SNPs) are known to influence the dietary requirement for choline. In this study, we examined a much larger number of SNPs (n=200) in 10 genes related to choline metabolism for associations with develop...
Research in obesity and metabolic disorders that involve intestinal microbiota demands reliable methods for the precise measurement of the short-chain fatty acids (SCFAs) and branched-chain amino acids (BCAAs) concentration. Here, we report a rapid method of simultaneously determining SCFAs and BCAAs in biological samples using propyl chloroformate...
This study evaluated dietary intake in children with fetal alcohol spectrum disorders (FASD). Pre-clinical research suggests that nutrient supplementation may attenuate cognitive and behavioral deficits in FASD. Currently, the dietary adequacy of essential nutrients in children with FASD is unknown. Dietary data were collected as part of a randomiz...
Mass spectrometry coupled to gas chromatography (GC-MS) has been widely applied in the field of metabolomics. Success of this application has benefited greatly from computational workflows that process the complex raw mass spectrometry data and extract the qualitative and quantitative information of metabolites. Among the computational algorithms w...
Our understanding of the bile acid metabolism is limited by the fact that previous analyses have primarily focused on a selected few circulating bile acids; the bile acid profiles of the liver and gastrointestinal tract pools are rarely investigated. Here, we determined how chronic ethanol consumption altered the bile acids in multiple body compart...
Women, during pregnancy and lactation, should eat foods that contain adequate amounts of choline. A mother delivers large amounts of choline across the placenta to the fetus, and after birth she delivers large amounts of choline in milk to the infant; this greatly increases the demand on the choline stores of the mother. Adequate intake of dietary...
Background: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian...
Choline dehydrogenase (CHDH) catalyzes the conversion of choline to betaine. Betaine is an osmolyte and an important methyl‐group donor. Previously, increased availability of choline to fetal brain resulted in increased hippocampal neurogenesis. The proposed mechanism involved epigenetic changes in genes that regulate cell proliferation. To determi...
Betaine homocysteine methyltransferase (BHMT) is responsible for the utilization of betaine, a metabolite of choline, as a methyl donor. We previously demonstrated that Bhmt knockout (KO) mice display several metabolic changes including alterations to the bile acid pool, insulin sensitivity, increased energy expenditure, hepatic steatosis and reduc...
Purpose of review:
Humans eating diets low in choline develop fatty liver and liver damage. Rodents fed choline-methionine-deficient diets not only develop fatty liver, but also progress to develop fibrosis and hepatocarcinoma. This review focuses on the role of choline in liver function, with special emphasis on the epigenetic mechanisms of actio...
Choline metabolism is important for very low-density lipoprotein secretion, making this nutritional pathway an important contributor to hepatic lipid balance. The purpose of this study was to assess whether the cumulative effects of multiple single nucleotide polymorphisms (SNPs) across genes of choline/1-carbon metabolism and functionally related...
Background:
Choline is essential for fetal brain development, and it is not known whether a typical American diet contains enough choline to ensure optimal brain development.
Objective:
The study was undertaken to determine whether supplementing pregnant women with phosphatidylcholine (the main dietary source of choline) improves the cognitive a...
In 1850, Theodore Gobley, working in Paris, described a substance, 'lecithine', which he named after the Greek 'lekithos' for egg yolk. Adolph Strecker noted in 1862 that when lecithin from bile was heated, it generated a new nitrogenous chemical that he named 'choline'. Three years later, Oscar Liebreich identified a new substance, 'neurine', in t...
Abstract There are multiple identified mechanisms involved in energy metabolism, insulin resistance and adiposity, but there are here-to-fore unsuspected metabolic factors that also influence these processes. Studies in animal models suggest important links between choline/1-carbon metabolism and energy homeostasis. Rodents fed choline deficient di...
The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Research Workshop, "Using Nutrigenomics and Metabolomics in Clinical Nutrition Research," was held on January 21, 2012, in Orlando, Florida. The conference brought together experts in human nutrition who use nutrigenomic and metabolomic methods to better understand metabolic ind...
Elevated homocysteine (Hcy) concentrations are associated with increased risk of several chronic diseases. Hcy can be removed by methylating it to form methionine via either the betaine homocysteine S-methyltransferase (BHMT) or the methionine synthase (MS) pathway. BHMT uses betaine as the methyl donor, whereas MS uses 5-methyltetrahydrofolate. We...
Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline-a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer.
Our objective was to exa...
Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SA...
Choline is an essential nutrient for numerous biological functions. Experience derived from research on choline has pioneered a new way of thinking about nutrition requirements for optimal health. This body of knowledge has demonstrated that the dietary need for choline is highly individual, and is based on several factors including genetics and ge...
Advances in nutrigenetics and nutrigenomics have been instrumental in demonstrating that nutrient requirements vary among individuals. This is exemplified by studies of the nutrient choline, in which gender, single-nucleotide polymorphisms, estrogen status, and gut microbiome composition have been shown to influence its optimal intake level. Cholin...
One of the underlying mechanisms for metabolic individuality is genetic variation. Single nucleotide polymorphisms (SNPs) in genes of metabolic pathways can create metabolic inefficiencies that alter the dietary requirement for, and responses to, nutrients. These SNPs can be detected using genetic profiling and the metabolic inefficiencies they cau...
Approximately 15% of couples are affected by infertility and up to half of these cases arise from male factor infertility. Unidentified genetic aberrations such as chromosomal deletions, translocations and single nucleotide polymorphisms (SNPs) may be the underlying cause of many cases of idiopathic male infertility. Deletion of the choline dehydro...
Oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) in Chdh+/+ and Chdh−/− sperm. Sperm were released from the cauda epididymides from Chdh+/+ and Chdh−/− male mice into modified HFT media. Modified HTF did not contain sodium bicarbonate, but did contain 1 mM Sp-5,6-dichloro-1- beta-D- ribofuranosylbenzimidazole-3′,5′-monoph...
Choline metabolite concentrations in Chdh+/+ and Chdh−/− epididymis.
Chdh+/+ and Chdh−/− male mice, at least 10 weeks of age were anesthetized using Isofluorane until they no longer respond to a pain stimulus. Caput, corpus and cauda epididymides were collected; both whole epididymides were pooled together for each animal. Tissues were snap frozen...
Health questionnaire form. All subjects completed the health questionnaire form during the screen visit.
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PtdCho and GPCho are decreased in Chdh−/− sperm.
Chdh+/+ and Chdh−/− male mice, at least 10 weeks of age, were anesthetized using Isofluorane until they no longer responded to a pain stimulus. Sperm were released into HTF media from the cauda epididymis as described previously. After 2 hour incubation in HTF, 4 million sperm from each animal were p...
We previously demonstrated that single nucleotide polymorphisms (SNPs) in the phosphatidylcholine (PtdCho) flippase ABCB4 were associated with obesity and proposed that PtdCho metabolism is a key player in energy metabolism. We sought to identify patterns of SNPs in one carbon metabolism, and related pathways, that are associated with obesity by ut...
Excess dietary choline has been implicated in increased cardiovascular disease (CVD) risk, a process mediated by bacterial catabolism of choline to trimethylamine N‐oxide (TMAO). To determine whether variation in dietary choline leads to differences in plasma TMAO and CVD risk in human subjects, we enrolled twenty female participants in a two‐month...
Physicians encounter nutrition challenges in their clinical practice on a daily basis. They need an easily accessible training source. The Nutrition in Medicine project is already providing nutrition education for a majority of US medical schools and many international schools. A new series of online nutrition instruction modules is now available f...
Betaine homocysteine S ‐methyltransferase (BHMT) catalyzes the conversion of homocysteine to methionine and is predominantly found in the liver. Mice with the gene encoding Bhmt deleted ( Bhmt −/− ) had reduced adiposity, smaller adipocytes, better glucose tolerance and enhanced insulin sensitivity than the controls. The reduced adiposity in Bhmt −...
Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the synthesis of methionine from homocysteine. In our initial report, we observed a reduced
body weight in Bhmt−/− mice. We initiated this study to investigate the potential role of BHMT in energy metabolism. Compared with the controls
(Bhmt+/+), Bhmt−/− mice had less fat mass, smaller adipo...
Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years, there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understandin...
Dietary choline is an important modulator of gene expression (via epigenetic marks) and of DNA integrity. Choline was discovered to be an essential nutrient for some humans approximately one decade ago. This requirement is diminished in young women because estrogen drives endogenous synthesis of phosphatidylcholine, from which choline can be derive...
Considerable evidence from epidemiological and clinical studies demonstrated that maternal nutritional status is closely associated with placental, embryonic, fetal growth and development, and ultimately pregnancy outcomes. In recent years, there has been a growing interest in the study of disorders of pregnancy using a metabolomic profiling approa...
