Dr. Steven H. Zeisel
Dr. Zeisel and his research team focus on the essential nutrient choline. In studies on this nutrient they are developing new concepts on why there are individual differences in nutrient metabolism by using new approaches in nutrigenomics and in metabolomics. Also, the Zeisel team studies nutrient effects on brain development and memory. The team works with humans, mice and cell culture model systems. Mass spectrometry, HPLC, molecular biologic methods and informatics tools are all used in this work.
In an NIH-funded study we are determining the human dietary requirements for choline. Subjects are hospitalized in a research facility, fed carefully defined diets in which we remove choline, and we determine whether they develop liver or muscle dysfunction (using MRI and clinical blood tests) that reverses when we restore dietary choline. We found that most men and postmenopausal women developed organ dysfunction on low choline, but only 40% of young women did. We discovered that the gene in liver that is responsible for producing choline from scratch, PEMT, has a promoter sequence (switch) in front of it that is turned on by estrogen. We identified the DNA coding sequence for this switch and are currently asking whether phytoestrogens and drug analogs of estrogen can induce this gene. Using our human studies we discovered that there are very common single nucleotide polymorphisms (SNPs; gene misspellings) that make humans require more dietary choline. One of these SNPs is in the gene PEMT (discussed above) and prevents estrogen from inducing the gene. This SNP occurs in more than half the population. Another SNP in folic acid metabolism causes an increased demand for choline and thereby increases by 85-fold the likelihood that a person will becomes sick when deprived of choline. We are currently examining whether there are copy number variations in these important genes of choline metabolism. We are collaborating in a number of epidemiology studies that examine the relationship between diet, these gene SNPs, and risk for breast cancer, colon cancer, birth defects and heart disease. The Zeisel team, after identifying a SNP of interest, makes a knockout mouse model with which to further study phenotypes that might occur in humans. We now have three such knockouts. One of them develops mitochondrial abnormalities and has immotile sperm. We plan studies in humans to see if SNPs in this gene result in male infertility.
In another NIH-funded study, the Zeisel team examines choline’s role in brain development. We know that, in mice and rats, extra choline fed pregnant dams, results in offspring who are smarter on maze testing. We discovered that the progenitor cells that become neurons in brain hippocampus (memory center) proliferate faster if they are exposed to more choline; at the same time they die slower by apoptosis. One explanation may be that choline changes epigenetic marks on DNA, thereby changing expression of genes regulating cell division and apoptosis. We found that, indeed, changing dietary choline in pregnant mice changes DNA and histone methylation in neuronal stem cells of fetal brain and that this directly alters cell cycle. We just discovered that the same is true for endothelial stem cells in fetal brain, thereby altering angiogenesis (blood vessel formation). The Zeisel team is currently exploring an alternative hypothesis, that PEMT in fetal brain is very active and that it is the major route for incorporating docosahexaenoic acid into brain. This essential fatty acid is known to be needed for brain development. We are starting new projects to examine whether choline influenced development of the retina, and to determine whether choline can change rates of stem cell proliferation in adult brain.
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Current Research Staff:
Heather (Xueqing) Zhao