Choline Deficiency–Induced Liver Damage Is Reversible in Pemt−/− Mice

Waite, Kristin; Cabilio, Nora R.; Vance, Dennis E.

doi:10.1093/jn/132.1.68

Cited by 76 publications

(65 citation statements)

References 14 publications

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“…Activities of AST and ALT in plasma, as indicators of hepatocytes damage (Waite et al 2002), were measured by spectrophotometer (Biosystems, BTS-330) and commercial kits (Sigma Chem. Co. St. Louis, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Co. St. Louis, USA). Plasma corticosterone concentration, as an indicator of stress (Waite et al 2002), was measured by radioimmunoassay using tubes labeled with rabbit anti-corticosterone-antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore we have performed experiment on rats and examined the effects of different levels of chronic CR and acute fasting on OS parameters in rat liver and plasma, in order to better understand mechanism of hormetic effect of CR. Additionally, plasma corticosterone concentration was measured as an indicator of stress and activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in plasma were measured as indicators of hepatocytes damage (Waite et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Effects of caloric restriction on oxidative stress parameters

Stanković

Mladenović²,

Ninković³

et al. 2013

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Abstract. Moderate caloric restriction prolongs lifespan. Changes in oxidative stress and hormesis may be involved in this process. The aim of this study is to examine the effects of different levels of chronic caloric restriction (CR) and acute fasting on stress response and oxidative stress parameters in rat liver and plasma. Forty-two rats were divided into groups: control group, calorie-restricted groups with intake of 80-90%, 60-70%, 40-50%, 20-30% of daily caloric needs and acute fasting group. To determine alanine aminotransferase (ALT), aspartate aminotransferase (AST) and superoxide dismutase (SOD) activity, concentration of corticosterone, nitrites and nitrates (NO x ), malondialdehyde (MDA) and glutathione (GSH), liver samples and blood were collected. Increase in plasma corticosterone concentration and AST and ALT activity was found in severe CR. Ingestion 40-50% daily caloric needs or less increased liver MDA and NO x concentration and decreased SOD activity. Ingestion 60-70% daily caloric needs increased Mn-SOD activity, GSH and NO x . In acute fasting group and group taking 20-30% daily caloric needs, GSH was significantly lower than in control group. Severe CR and acute fasting increase oxidative damage and decrease antioxidative capacity of hepatocytes. Moderate CR increases antioxidative capacity of hepatocytes due to increase in Mn-SOD activity and GSH concentration, which might have a role in anti-aging and hormetic mechanism of CR.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of caloric restriction on oxidative stress parameters

Stanković

Mladenović²,

Ninković³

et al. 2013

gpb

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“…We compared these values to those for the phosphatidylethanolamine methyltransferase (PEMT), which governs the alternate pathway for PtdCho synthesis in liver (52), to obtain a sense of the relative contributions of each of these proteins to PtdCho synthesis overall. We found that CCT␤2 and CCT␤3, if expressed, constitute a minor species in most tissue CCT pools, except for brain tissue.…”

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confidence: 99%

Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

Jackowski

Rehg

Zhang³

et al. 2004

Molecular and Cellular Biology

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There are two mammalian genes that encode isoforms of CTP:phosphocholine cytidylyltransferase (CCT), a key rate-controlling step in membrane phospholipid biogenesis. Quantitative determination of the CCT transcripts reveals that CCT␣ is ubiquitously expressed and is found at the highest levels in the testis and lung, with lower levels in the liver and ovary. CCT␤2 is a very minor isoform in most tissues but is significantly expressed in the brain, lung, and gonads. CCT␤3 is the third isoform recently discovered in mice and is expressed in the same tissues as CCT␤2, with its highest level in testes. We investigated the role(s) of CCT␤2 by generating knockout mice. The brains and lungs of mice lacking CCT␤2 expression did not exhibit any overt defects. On the other hand, a large percentage of the CCT␤2 ؊/؊ females were sterile and their ovaries exhibited defective ovarian follicle development. The proportion of female CCT␤2 ؊/؊ mice with defective ovaries increased as the animals aged. The rare litters born from CCT␤2 ؊/؊ ؋ CCT␤2 ؊/0 matings had the normal number of pups. The abnormal ovarian histopathology was characterized by disorganization of the tissue in young adult mice and absence of follicles and ova in older mice, along with interstitial stromal cell hyperplasia which culminated in the emergence of tubulostromal ovarian tumors by 16 months of age. Grossly defective CCT␤2 ؊/؊ ovaries were associated with high follicle-stimulating (FSH) and luteinizing (LH) hormone levels. Male CCT␤2 ؊/0 mice exhibited progressive multifocal testicular degeneration and reduced fertility but had normal FSH and LH levels. Thus, the most notable phenotype of CCT␤2 knockout mice was gonad degeneration and reproductive deficiency. The results indicate that although CCT␤2 is expressed at very low levels compared to the ␣-isoform, loss of CCT␤2 expression causes a breakdown in the gonadal response to hormonal stimulation.Phosphatidylcholine (PtdCho) is a major component of biological membranes in higher eukaryotes and is also secreted by specialized tissues for important extracellular tasks. CTP: phosphocholine cytidylyltransferase (CCT) is a key rate-controlling step in the major biosynthetic pathway leading to PtdCho in most tissues (for reviews, see references 15, 17, and 36). In mammals there are two genes, Pcyt1a (formerly Cptct), located on murine chromosome 16, and Pcyt1b, located on the X chromosome, that encode proteins termed CCT␣ and CCT␤, respectively (35, 38). The two genes exhibit tissuespecific expression, with CCT␣ predominating in most tissues and CCT␤ being most abundant in brain tissue (32). Two transcripts arise from the Pcyt1a gene that encode the identical CCT␣ protein. Alternate splicing of the X-linked Pcyt1b gene directs the synthesis of two mRNAs that encode the CCT␤2 and CCT␤3 isoforms in mice (32,35,38). CCT␤3 is 28 residues shorter at the amino terminus than CCT␤2 due to transcript initiation at an alternate first exon (32). In humans, intron retention gives rise to a CCT␤1 transcript found in the exp...

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“…This enzyme uses S-adenosylmethionine as a methyl donor and forms a new choline moiety (37). When fed a diet deficient in choline, Pemt 7/7 mice developed fatty liver, severe liver damage and died; a choline supplemented diet prevented this (38) and reversed hepatic damage if begun early enough (39). The PEMT pathway is not just a minor pathway that backs up the cytidine diphosphocholine pathway for phosphatidylcholine biosynthesis.…”

Section: Dietary Intake and Endogenous Synthesis Of Cholinementioning

confidence: 99%

Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline

Zeisel

2007

IUBMB Life

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SummaryRecent progress in the understanding of the human dietary requirement for choline highlights the importance of genetic variation and epigenetics in human nutrient requirements. Choline is a major dietary source of methyl-groups (one of choline's metabolites, betaine, participates in the methylation of homocysteine to form methionine); also choline is needed for the biosynthesis of cell membranes, bioactive phospholipids and the neurotransmitter acetylcholine. A recommended dietary intake for choline in humans was set in 1998, and a portion of the choline requirement can be met via endogenous de novo synthesis of phosphatidylcholine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT) in the liver. Though many foods contain choline, many humans do not get enough in their diets. When deprived of dietary choline, most adult men and postmenopausal women developed signs of organ dysfunction (fatty liver, liver or muscle cell damage, and reduces the capacity to handle a methionine load, resulting in elevated homocysteine). However, only a portion of premenopausal women developed such problems. The difference in requirement occurs because estrogen induces expression of the PEMT gene and allows premenopausal women to make more of their needed choline endogenously. In addition, there is significant variation in the dietary requirement for choline that can be explained by common polymorphisms in genes of choline and folate metabolism. Choline is critical during fetal development, when it alters DNA methylation and thereby influences neural precursor cell proliferation and apoptosis. This results in long term alterations in brain structure and function, specifically memory function. IUBMB Life, 59: 380-387, 2007

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Choline Deficiency–Induced Liver Damage Is Reversible in Pemt−/− Mice

Cited by 76 publications

References 14 publications

Effects of caloric restriction on oxidative stress parameters

Effects of caloric restriction on oxidative stress parameters

Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline

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