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Donald M Mock - One of the best experts on this subject based on the ideXlab platform.
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in hepg2 cells coexisting carnitine Deficiency masks important indicators of marginal Biotin Deficiency
Journal of Nutrition, 2015Co-Authors: Anna Bogusiewicz, Gunnar Boysen, Donald M MockAbstract:Background: A large number of birth defects are related to nutrient deficiencies; concern that Biotin Deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of Biotin Deficiency, is not a valid biomarker in pregnancy. Objective: In this study we hypothesized that coexisting carnitine Deficiency can prevent the increase in 3HIAc due to Biotin Deficiency. Methods: We used a 2-factor nutrient depletion design to induce isolated and combined Biotin and carnitine Deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography–tandem mass spectrometry. Results: Relative to Biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in Biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which Biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the Biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In Biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked Biotin Deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased by >8-fold. Conclusions: Our findings provide strong evidence that coexisting carnitine Deficiency masks some indicators of Biotin Deficiency and support the potential importance of the ratios of acylcarnitines arising from the acyl-CoA substrates and products for Biotin-dependent carboxylases in detecting the Biotin Deficiency that is masked by coexisting carnitine Deficiency.
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marginal Biotin Deficiency can be induced experimentally in humans using a cost effective outpatient design
Journal of Nutrition, 2012Co-Authors: Shawna L Stratton, Anna Bogusiewicz, Gunnar Boysen, Cindy L Henrich, Thomas D Horvath, Nell I Matthews, Jeffery H Moran, Amanda M Dawson, Suzanne N Owen, Donald M MockAbstract:To date, marginal, asymptomatic Biotin Deficiency has been successfully induced experimentally by the use of labor-intensive inpatient designs requiring rigorous dietary control. We sought to determine if marginal Biotin Deficiency could be induced in humans in a less expensive outpatient design incorporating a self-selected, mixed general diet. We sought to examine the efficacy of three outpatient study designs: two based on oral avidin dosing and one based on a diet high in undenatured egg white for a period of 28 d. In study design 1, participants (n = 4; 3 women) received avidin in capsules with a Biotin binding capacity of 7 times the estimated dietary Biotin intake of a typical self-selected diet. In study design 2, participants (n = 2; 2 women) received double the amount of avidin capsules (14 times the estimated dietary Biotin intake). In study design 3, participants (n = 5; 3 women) consumed egg-white beverages containing avidin with a Biotin binding capacity of 7 times the estimated dietary Biotin intake. Established indices of Biotin status [lymphocyte propionyl-CoA carboxylase activity; urinary excretion of 3-hydroxyisovaleric acid, 3-hydroxyisovaleryl carnitine (3HIA-carnitine), and Biotin; and plasma concentration of 3HIA-carnitine] indicated that study designs 1 and 2 were not effective in inducing marginal Biotin Deficiency, but study design 3 was as effective as previous inpatient study designs that induced Deficiency by egg-white beverage. Marginal Biotin Deficiency can be induced experimentally by using a cost-effective outpatient design by avidin delivery in egg-white beverages. This design should be useful to the broader nutritional research community.
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urinary excretion of 3 hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal Biotin Deficiency in humans
Journal of Nutrition, 2011Co-Authors: Shawna L Stratton, Anna Bogusiewicz, Cindy L Henrich, Thomas D Horvath, Nell I Matthews, Horace J Spencer, Jeffery H Moran, Donald M MockAbstract:Mounting evidence indicates that marginal Biotin Deficiency is not rare, contrary to previous assumptions. Accordingly, robust indicators of Biotin status would be useful. In a study of 10 healthy adults, we recently provided evidence that abnormally increased plasma concentration of 3-hydroxyisovaleryl carnitine (3HIA-carnitine) is a sensitive indicator of marginal Biotin Deficiency. We sought to determine whether urinary excretion of 3HIA-carnitine (expressed as the ratio to urinary creatinine) significantly increases in marginal Biotin Deficiency. Marginal, asymptomatic Biotin Deficiency was induced experimentally in the same 10 healthy adults (8 women) by feeding undenatured egg white with meals for 28 d. Biotin status was repleted by a mixed general diet plus Biotin supplementation. Urinary excretion of 3HIA-carnitine was determined by liquid chromatography-tandem MS on d 0, 14, and 28 (depletion) and on d 35 and 50 (repletion). Mean urinary 3HIA-carnitine concentration increased with depletion (P < 0.0001; d 0 vs. 28) and decreased with repletion (P = 0.0002; d 28 vs. 50). Urinary 3HIA-carnitine excretion was greater than the upper limit of normal in 9 of 10 participants by d 14 and decreased to within normal limits by d 50 in all participants. This study provides evidence that urinary excretion of 3HIA-carnitine is an early and sensitive indicator of marginal Biotin Deficiency. The ease of collection of untimed urine samples and application of a new analytical method with simplified sample preparation suggest that urinary 3HIA-carnitine is likely to be a useful indicator for large population studies.
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plasma concentration of 3 hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal Biotin Deficiency in humans
The American Journal of Clinical Nutrition, 2010Co-Authors: Shawna L Stratton, Anna Bogusiewicz, Cindy L Henrich, Thomas D Horvath, Nell I Matthews, Horace J Spencer, Jeffery H Moran, Donald M MockAbstract:Background: Blood-based indicators of Biotin status in humans were shown to be useful tools in several clinical situations, including pregnancy. We previously validated the activity of the Biotindependent enzyme propionyl-coenzyme A carboxylase (PCC) in lymphocytes as a sensitive and specific blood-based indicator of marginal degrees of Biotin Deficiency. However, the measurement of PCC activity in population studies presents substantial analytic challenges. 3-Hydroxyisovaleryl carnitine (3HIA-carnitine) increases in response to the decreased activity of the Biotin-dependent enzyme methylcrotonyl-coenzyme A carboxylase and might reflect Biotin status. Objective: We sought to determine whether the plasma concentration of 3HIA-carnitine increases significantly in marginal Biotin Deficiency. Design: We experimentally induced marginal, asymptomatic Biotin Deficiency in 10 healthy adults (8 women) by having the subjects consume undenatured egg white for 28 d; Biotin status was then repleted. Plasma concentrations of 3HIA-carnitine were measured on days 0, 14, 28, 35, and 50 by liquid chromatography‐mass spectroscopy. Results: The mean plasma 3HIA-carnitine concentration increased with depletion (P , 0.0001) and decreased with repletion (P , 0.0001). Plasma 3HIA-carnitine concentrations were greater than the upper limit of normal concentrations in 7 of 10 subjects by day 14 and in 9 of 10 subjects by day 28 and decreased to within normal limits in 9 of 10 subjects by day 50. Conclusions: These studies provide evidence that 3HIA-carnitine is an early and sensitive indicator of marginal Biotin Deficiency. The ease of sample collection, small sample volume requirement, and stability of 3HIA-carnitine during storage suggest that the plasma 3HIA-carnitine concentration is likely to be a useful indicator of marginal Biotin Deficiency for larger population studies. Am J Clin Nutr doi: 10.3945/ajcn.110.002543.
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marginal Biotin Deficiency is common in normal human pregnancy and is highly teratogenic in mice
Journal of Nutrition, 2009Co-Authors: Donald M MockAbstract:In studies of marginal Biotin Deficiency induced experimentally in adults, increased urinary excretion of 3-hydroxyisovaleric acid (3HIA), which likely reflects decreased activity of the Biotin-dependent enzyme β-methylcrotonyl-CoA carboxylase, and decreased activity of the Biotin-dependent enzyme propionyl-CoA carboxylase (PCC) in peripheral blood lymphocytes have been validated as indices of Biotin status. About half of pregnant women excrete increased amounts of urinary 3HIA. However, interpretation of urinary 3HIA excretion rates is problematic, because renal function is altered by pregnancy per se. In a recent pilot study, activity of PCC in peripheral blood lymphocytes was decreased in 18 of 22 pregnant women. In 4 of 4 pregnant women with decreased PCC activity, Biotin supplementation caused increased PCC activity by a mean of 95%. Taken together, such studies provide evidence that a substantial proportion of pregnant women are marginally Biotin deficient. In mice, degrees of Biotin Deficiency that are metabolically similar to those seen in pregnant women are very teratogenic. Moreover, in mice, a marginal degree of Biotin Deficiency in the dam causes a much more severe degree of Deficiency in the fetus. These observations further raise concerns that Biotin Deficiency does occur and does cause human birth defects.
Nell I Mock - One of the best experts on this subject based on the ideXlab platform.
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Biotin Deficiency reduces expression of SLC19A3, a potential Biotin transporter, in leukocytes from human blood
Experimental biology, 2020Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M. MocksAbstract:In evaluating potential indicators of Biotin status, we quantitated the expression of Biotin-related genes in leukocytes from human blood of normal subjects before and after inducing marginal Biotin Deficiency. Biotin Deficiency was induced experimentally by feeding an egg-white diet for 28 d. Gene expression was quantitated for the following Biotin-related proteins: methylcrotonyl-CoA carboxylase chains A (MCCA) and B (MCCB); propionyl-CoA carboxylase chains A (PCCA) and B (PCCB); pyruvate carboxylase (PC); acetyl-CoA carboxylase isoforms A (ACCA) and B (ACCB); holocarboxylase synthetase (HCS); Biotinidase; and 2 potential Biotin transporters: sodium-dependent multivitamin transporter (SMVT) and solute carrier family 19 member 3 (SLC19A3). For 7 subjects who successfully completed the study, the abundance of the specific mRNAs was determined by quantitative real-time RT-PCR at d 0 and 28. At d 28, SLC1 9A3 expression had decreased to 33% of d 0 (P < 0.02 by two-tailed, paired t test). Expression of MCCA, PCCA, PC, ACCA, ACCB, HCS, Biotinidase, and SMVT decreased to ∼80% of d 0 (P < 0.05). Expression of the MCCB and PCCB chains that do not carry the Biotin-binding motif did not change significantly; we speculate that expression of the Biotin-binding chains of Biotin-dependent carboxylases is more responsive to Biotin status changes. These data provide evidence that expression of SLC19A3 is a relatively sensitive indicator of marginal Biotin Deficiency.
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lymphocyte propionyl coa carboxylase and its activation by Biotin are sensitive indicators of marginal Biotin Deficiency in humans
The American Journal of Clinical Nutrition, 2006Co-Authors: Shawna L Stratton, Nell I Mock, Anna Bogusiewicz, Amanda M Wells, Matthew M Mock, Donald M MockAbstract:BACKGROUND: Marginal Biotin Deficiency may be a human teratogen. A Biotin status indicator that is not dependent on renal function may be useful in studies of Biotin status during pregnancy. A previous study of experimental Biotin Deficiency suggested that propionyl-coenzyme A carboxylase (PCC) activity in peripheral blood lymphocytes (PBLs) is a sensitive indicator of Biotin status. OBJECTIVE: We examined the utility of measuring PCC activity and the activation of PCC by Biotin in detecting marginal Biotin Deficiency. DESIGN: Marginal Biotin Deficiency was induced in 7 adults (3 women) by egg-white feeding for 28 d. Blood and urine were obtained on days 0, 14, and 28 (depletion phase) and 44 and 65 (repletion phase). PBLs were incubated with (activated) or without (control) Biotin before PCC assay. The activation coefficient of PCC is the ratio of PCC activity in activated PBLs to that in control PBLs. The significance of differences for all measurements was tested by repeated-measures analysis of variance with Fisher's post hoc test and Bonferroni correction. RESULTS: Changes in the urinary excretion of Biotin and of 3-hydroxyisovaleric acid confirmed that marginal Biotin Deficiency was successfully induced. By day 14, PCC activity had decreased (P < 0.0001) to below the lower limit of normal in all subjects. By day 28, the activation coefficient of PCC had increased significantly (P = 0.003) and was above the upper limit of normal in 6 of 7 subjects. CONCLUSION: PCC activity is the most sensitive indicator of Biotin status tested to date. In future pregnancy studies, the use of lymphocyte PCC activity data should prove valuable in the assessment of Biotin status.
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Biotin Deficiency reduces expression of slc19a3 a potential Biotin transporter in leukocytes from human blood
Journal of Nutrition, 2005Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M MockAbstract:Biotin Deficiency is teratogenic in mice (1,2) and may be teratogenic in humans (3). Valid indicators of marginal and moderate Biotin Deficiency would be useful in investigating the role of Biotin Deficiency in birth defects and in other illnesses hypothesized to be Biotin related (4 –7). Emerging evidence indicates that Biotin plays a role in gene expression (8 –12). In addition to acting as a cofactor for Biotin-dependent carboxylases, Biotin stimulates expression of hepatic glucokinase (8) and represses expression of hepatic phosphoenolpyruvate carboxylase (9) in vivo, and expression of the Biotin-related enzymes propionyl-CoA carboxylase chain A (PCCA),4 acetyl-CoA carboxylase isoform A (ACCA), and holocarboxylase synthetase (HCS) in cultured human hepatoblastoma cells and normal fibroblasts (10). However, no such studies have been performed in humans in vivo. In this study, we examined the expression of specific Biotin-related genes as indicators of marginal, asymptomatic Biotin Deficiency and assessed gene response to marginal Biotin Deficiency. In mammals, Biotin is a coenzyme for 5 Biotin-dependent carboxylases: methylcrotonyl-CoA carboxylase (MCC), propionyl-CoA carboxylase (PCC), pyruvate carboxylase (PC), and the 2 isoforms of ACC (ACCA and ACCB). The active forms of the enzymes (holocarboxylases) contain Biotin covalently bound to lysine residues; the attachment of Biotin to the corresponding apocarboxylase is catalyzed by HCS. Biotin is transported into eukaryotic cells by Biotin transporters located in cell membranes. Three Biotin transporters have been proposed in human cells: 1) the sodium-dependent multivitamin transporter (SMVT) (13,14); 2) the solute carrier family 19 member 3 (SLC19A3) (15,16); and 3) the monocarboxylate transporter R1 (17). This third transporter was proposed after this study was initiated and was not examined here. Biotinidase catalyzes the release of covalently bound Biotin from Biotinyl-peptides generated by the turnover of intracellular proteins and releases Biotin from dietary proteins during digestion (18). Biotinidase is also likely important in catalyzing the covalent binding of Biotin to histones (19). In this study, we evaluated expression of Biotin-related genes as potential indicators of marginal, asymptomatic Biotin Deficiency. Gene expression was quantitated in leukocytes of 7 healthy humans after 28 d of progressive Biotin Deficiency.
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3 hydroxypropionic acid and methylcitric acid are not reliable indicators of marginal Biotin Deficiency in humans
Journal of Nutrition, 2004Co-Authors: Donald M Mock, Nadine Carnell, Cindy L Henrichshell, Phyllis J Stumbo, Nell I MockAbstract:In two studies comprising 10 and 11 subjects, respectively, marginal Biotin Deficiency was induced experimentally by an egg-white diet in healthy men and women. The following urinary organic acids were assessed for their usefulness in detecting marginal Biotin status: 1) 3-hydroxypropionic acid and methylcitric acid, organic acids that reflect decreased activity of the Biotin-dependent enzyme propionyl-CoA carboxylase and 2) methylcrotonylglycine and isovalerylglycine, organic acids that reflect decreased activity of methylcrotonyl-CoA carboxylase. Mean 3-hydroxypropionic acid excretion rates remained normal during Biotin depletion in both studies. By the end of the depletion period, 3-hydroxypropionic acid excretion identified only 5 of 21 marginally deficient subjects. Mean methylcitric acid excretion increased (P < 0.0001) in the first study but not in the second. Mean methylcrotonylglycine excretion increased in each study (P < 0.004 and P < 0.05, respectively); methylcrotonylglycine excretion identified 13 of 21 marginally deficient subjects. Mean isovalerylglycine excretion increased only in the first study (P = 0.006) and identified only 6 of 21 deficient subjects. We conclude that none of these organic acids is as sensitive an indicator of marginal Biotin Deficiency as 3-hydroxyisovaleric acid, which reflects decreased methylcrotonyl-CoA carboxylase.
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marginal Biotin Deficiency is teratogenic in icr mice
Journal of Nutrition, 2003Co-Authors: Donald M Mock, Nell I Mock, Christopher W Stewart, James B Laborde, Deborah K HansenAbstract:: The incidence of marginal Biotin Deficiency in normal human gestation is approximately one in three. In ICR mice, maternal Biotin Deficiency results in cleft palate, micrognathia, microglossia and limb hypoplasia. However, the relationships among the severity of maternal Biotin Deficiency, fetal Biotin status and malformations have not been reported. This study utilized validated indices of Biotin status to investigate the relationships among maternal Biotin status, fetal Biotin status and the rate of fetal malformations in ICR mice. Biotin status was controlled by feeding diets with varying egg white concentration. In dams and fetuses, Biotin status was assessed by hepatic Biotin content and hepatic activity of the Biotin-dependent enzyme propionyl-CoA carboxylase; in dams, status was also assessed by urinary excretion of Biotin and 3-hydroxyisovaleric acid. Malformations were assessed morphologically. Biotin was measured by HPLC/avidin-binding assay. Propionyl-CoA carboxylase (PCC) activity was determined by H(14)CO(3) incorporation. 3-Hydroxyisovaleric acid concentration was determined by GC/MS. Although no overt signs of Deficiency appeared, metabolic disturbances caused by Biotin Deficiency were detectable in dams and fetuses. These disturbances increased with increasing egg white. Fetal Biotin status correlated significantly with maternal Biotin status (fetal vs. dam hepatic Biotin, r = 0.671; fetal vs. dam PCC activity, r = 0.70). The incidences of malformations were strikingly dependent on egg white concentration. We conclude that in ICR mice, marginal maternal Biotin Deficiency causes fetal Biotin Deficiency. We speculate that the fetal malformations are primarily the consequence of fetal Biotin Deficiency. Because murine malformations appeared at degrees of Biotin Deficiency that are similar to those in human gestation, we speculate that some human fetal malformations may be caused by Biotin Deficiency.
Antonio Velazquezarellano - One of the best experts on this subject based on the ideXlab platform.
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functional and metabolic implications of Biotin Deficiency for the rat heart
Molecular Genetics and Metabolism, 2008Co-Authors: Antonio Velazquezarellano, Maria De La Luz Hernandezesquivel, Rafael Moreno Sanchez, Daniel Ortegacuellar, Nayeli Rodriguezfuentes, Saul Cano, Alfonso Leondelrio, Karla CarvajalAbstract:The tricarboxylic acid (TCA) cycle is the main ATP provider for the heart. TCA carbons must be replenished by anaplerosis for normal cardiac function. Biotin is cofactor of the anaplerotic enzymes pyruvate and propionyl-CoA carboxylases. Here, we found that in Biotin deficient rats, both carboxylases decreased 90% in adipose tissue, jejunum and spleen, but in heart they conserved about 60% residual activity. We then investigated if under Biotin Deficiency (BtDEF), the heart is able to maintain its function in vivo and in isolated conditions, and during ischemia and reperfusion, where metabolism drastically shifts from oxidative to mainly glycolytic. Neither glucose nor octanoate oxidation were severely affected in BtDEF hearts, as assessed by mechanical performance, oxygen uptake or high-energy metabolite content; however, myocardial hexokinase activity and lactate concentration were reduced in deficient hearts. When challenged by ischemia and reperfusion injury, BtDEF hearts did not suffer more damage than the controls, although they lowered significantly their performance, when changed to ischemic conditions, which may have clinical implications. Post-ischemic increase in ADP/ATP ratio was similar in both groups, but during reperfusion there was higher rhythm perturbation in BtDEF hearts. By being relatively insensitive to Biotin Deficiency, cardiac tissue seems to be able to replenish TCA cycle intermediates and to maintain ATP synthesis.
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Biotin Deficiency affects both synthesis and degradation of pyruvate carboxylase in rat primary hepatocyte cultures
Molecular Genetics and Metabolism, 2007Co-Authors: Nayeli Rodriguezfuentes, Itzel Lopezrosas, Gabriela Romancisneros, Antonio VelazquezarellanoAbstract:Abstract Pyruvate carboxylase (PC) is a Biotin-dependent enzyme that plays a crucial role in gluconeogenesis, lipogenesis, Krebs cycle anaplerosis and amino acid catabolism. Biotin Deficiency reduces its mass besides its activity. Enzyme mass is the result of its cellular turnover, i.e., its rates of synthesis and degradation. We have now investigated, by a pulse and chase approach in cultured primary hepatocytes, the effects of Biotin Deficiency on these rates. Wistar rats were fed a Biotin-deficient diet and the controls were fed the same diet supplemented with Biotin; their Biotin status was monitored measuring lymphocytes propionyl-CoA carboxylase activity and urinary 3-hydroxyisovaleric acid. After 6–7 weeks primary hepatocytes were cultured in Biotin-deficient or complete DMEM. PC activity was determined by measuring the incorporation of 14 C-bicarbonate into acid-non-volatile products, and its mass by streptavidin Western blots. Its synthesis rate was estimated from [ 35 S] methionine incorporation into anti-PC antibody immunoprecipitate. Its degradation rate was calculated from the loss of radioactivity from previously labeled hepatocytes, in a medium containing an excess of non-radioactive methionine. PC synthesis rate in Biotin-deficient hepatocytes was approximately 4.5-fold lower than in the controls, and its degradation rate was 5.1-fold higher. Therefore, the decrement of PC mass during Biotin Deficiency results both from a decrease in its synthesis and an increase in its degradation rates. To our knowledge, this is the first instance where a mammalian enzyme cofactor is necessary to sustain both processes.
Shawna L Stratton - One of the best experts on this subject based on the ideXlab platform.
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Biotin Deficiency reduces expression of SLC19A3, a potential Biotin transporter, in leukocytes from human blood
Experimental biology, 2020Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M. MocksAbstract:In evaluating potential indicators of Biotin status, we quantitated the expression of Biotin-related genes in leukocytes from human blood of normal subjects before and after inducing marginal Biotin Deficiency. Biotin Deficiency was induced experimentally by feeding an egg-white diet for 28 d. Gene expression was quantitated for the following Biotin-related proteins: methylcrotonyl-CoA carboxylase chains A (MCCA) and B (MCCB); propionyl-CoA carboxylase chains A (PCCA) and B (PCCB); pyruvate carboxylase (PC); acetyl-CoA carboxylase isoforms A (ACCA) and B (ACCB); holocarboxylase synthetase (HCS); Biotinidase; and 2 potential Biotin transporters: sodium-dependent multivitamin transporter (SMVT) and solute carrier family 19 member 3 (SLC19A3). For 7 subjects who successfully completed the study, the abundance of the specific mRNAs was determined by quantitative real-time RT-PCR at d 0 and 28. At d 28, SLC1 9A3 expression had decreased to 33% of d 0 (P < 0.02 by two-tailed, paired t test). Expression of MCCA, PCCA, PC, ACCA, ACCB, HCS, Biotinidase, and SMVT decreased to ∼80% of d 0 (P < 0.05). Expression of the MCCB and PCCB chains that do not carry the Biotin-binding motif did not change significantly; we speculate that expression of the Biotin-binding chains of Biotin-dependent carboxylases is more responsive to Biotin status changes. These data provide evidence that expression of SLC19A3 is a relatively sensitive indicator of marginal Biotin Deficiency.
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marginal Biotin Deficiency can be induced experimentally in humans using a cost effective outpatient design
Journal of Nutrition, 2012Co-Authors: Shawna L Stratton, Anna Bogusiewicz, Gunnar Boysen, Cindy L Henrich, Thomas D Horvath, Nell I Matthews, Jeffery H Moran, Amanda M Dawson, Suzanne N Owen, Donald M MockAbstract:To date, marginal, asymptomatic Biotin Deficiency has been successfully induced experimentally by the use of labor-intensive inpatient designs requiring rigorous dietary control. We sought to determine if marginal Biotin Deficiency could be induced in humans in a less expensive outpatient design incorporating a self-selected, mixed general diet. We sought to examine the efficacy of three outpatient study designs: two based on oral avidin dosing and one based on a diet high in undenatured egg white for a period of 28 d. In study design 1, participants (n = 4; 3 women) received avidin in capsules with a Biotin binding capacity of 7 times the estimated dietary Biotin intake of a typical self-selected diet. In study design 2, participants (n = 2; 2 women) received double the amount of avidin capsules (14 times the estimated dietary Biotin intake). In study design 3, participants (n = 5; 3 women) consumed egg-white beverages containing avidin with a Biotin binding capacity of 7 times the estimated dietary Biotin intake. Established indices of Biotin status [lymphocyte propionyl-CoA carboxylase activity; urinary excretion of 3-hydroxyisovaleric acid, 3-hydroxyisovaleryl carnitine (3HIA-carnitine), and Biotin; and plasma concentration of 3HIA-carnitine] indicated that study designs 1 and 2 were not effective in inducing marginal Biotin Deficiency, but study design 3 was as effective as previous inpatient study designs that induced Deficiency by egg-white beverage. Marginal Biotin Deficiency can be induced experimentally by using a cost-effective outpatient design by avidin delivery in egg-white beverages. This design should be useful to the broader nutritional research community.
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urinary excretion of 3 hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal Biotin Deficiency in humans
Journal of Nutrition, 2011Co-Authors: Shawna L Stratton, Anna Bogusiewicz, Cindy L Henrich, Thomas D Horvath, Nell I Matthews, Horace J Spencer, Jeffery H Moran, Donald M MockAbstract:Mounting evidence indicates that marginal Biotin Deficiency is not rare, contrary to previous assumptions. Accordingly, robust indicators of Biotin status would be useful. In a study of 10 healthy adults, we recently provided evidence that abnormally increased plasma concentration of 3-hydroxyisovaleryl carnitine (3HIA-carnitine) is a sensitive indicator of marginal Biotin Deficiency. We sought to determine whether urinary excretion of 3HIA-carnitine (expressed as the ratio to urinary creatinine) significantly increases in marginal Biotin Deficiency. Marginal, asymptomatic Biotin Deficiency was induced experimentally in the same 10 healthy adults (8 women) by feeding undenatured egg white with meals for 28 d. Biotin status was repleted by a mixed general diet plus Biotin supplementation. Urinary excretion of 3HIA-carnitine was determined by liquid chromatography-tandem MS on d 0, 14, and 28 (depletion) and on d 35 and 50 (repletion). Mean urinary 3HIA-carnitine concentration increased with depletion (P < 0.0001; d 0 vs. 28) and decreased with repletion (P = 0.0002; d 28 vs. 50). Urinary 3HIA-carnitine excretion was greater than the upper limit of normal in 9 of 10 participants by d 14 and decreased to within normal limits by d 50 in all participants. This study provides evidence that urinary excretion of 3HIA-carnitine is an early and sensitive indicator of marginal Biotin Deficiency. The ease of collection of untimed urine samples and application of a new analytical method with simplified sample preparation suggest that urinary 3HIA-carnitine is likely to be a useful indicator for large population studies.
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plasma concentration of 3 hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal Biotin Deficiency in humans
The American Journal of Clinical Nutrition, 2010Co-Authors: Shawna L Stratton, Anna Bogusiewicz, Cindy L Henrich, Thomas D Horvath, Nell I Matthews, Horace J Spencer, Jeffery H Moran, Donald M MockAbstract:Background: Blood-based indicators of Biotin status in humans were shown to be useful tools in several clinical situations, including pregnancy. We previously validated the activity of the Biotindependent enzyme propionyl-coenzyme A carboxylase (PCC) in lymphocytes as a sensitive and specific blood-based indicator of marginal degrees of Biotin Deficiency. However, the measurement of PCC activity in population studies presents substantial analytic challenges. 3-Hydroxyisovaleryl carnitine (3HIA-carnitine) increases in response to the decreased activity of the Biotin-dependent enzyme methylcrotonyl-coenzyme A carboxylase and might reflect Biotin status. Objective: We sought to determine whether the plasma concentration of 3HIA-carnitine increases significantly in marginal Biotin Deficiency. Design: We experimentally induced marginal, asymptomatic Biotin Deficiency in 10 healthy adults (8 women) by having the subjects consume undenatured egg white for 28 d; Biotin status was then repleted. Plasma concentrations of 3HIA-carnitine were measured on days 0, 14, 28, 35, and 50 by liquid chromatography‐mass spectroscopy. Results: The mean plasma 3HIA-carnitine concentration increased with depletion (P , 0.0001) and decreased with repletion (P , 0.0001). Plasma 3HIA-carnitine concentrations were greater than the upper limit of normal concentrations in 7 of 10 subjects by day 14 and in 9 of 10 subjects by day 28 and decreased to within normal limits in 9 of 10 subjects by day 50. Conclusions: These studies provide evidence that 3HIA-carnitine is an early and sensitive indicator of marginal Biotin Deficiency. The ease of sample collection, small sample volume requirement, and stability of 3HIA-carnitine during storage suggest that the plasma 3HIA-carnitine concentration is likely to be a useful indicator of marginal Biotin Deficiency for larger population studies. Am J Clin Nutr doi: 10.3945/ajcn.110.002543.
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lymphocyte propionyl coa carboxylase and its activation by Biotin are sensitive indicators of marginal Biotin Deficiency in humans
The American Journal of Clinical Nutrition, 2006Co-Authors: Shawna L Stratton, Nell I Mock, Anna Bogusiewicz, Amanda M Wells, Matthew M Mock, Donald M MockAbstract:BACKGROUND: Marginal Biotin Deficiency may be a human teratogen. A Biotin status indicator that is not dependent on renal function may be useful in studies of Biotin status during pregnancy. A previous study of experimental Biotin Deficiency suggested that propionyl-coenzyme A carboxylase (PCC) activity in peripheral blood lymphocytes (PBLs) is a sensitive indicator of Biotin status. OBJECTIVE: We examined the utility of measuring PCC activity and the activation of PCC by Biotin in detecting marginal Biotin Deficiency. DESIGN: Marginal Biotin Deficiency was induced in 7 adults (3 women) by egg-white feeding for 28 d. Blood and urine were obtained on days 0, 14, and 28 (depletion phase) and 44 and 65 (repletion phase). PBLs were incubated with (activated) or without (control) Biotin before PCC assay. The activation coefficient of PCC is the ratio of PCC activity in activated PBLs to that in control PBLs. The significance of differences for all measurements was tested by repeated-measures analysis of variance with Fisher's post hoc test and Bonferroni correction. RESULTS: Changes in the urinary excretion of Biotin and of 3-hydroxyisovaleric acid confirmed that marginal Biotin Deficiency was successfully induced. By day 14, PCC activity had decreased (P < 0.0001) to below the lower limit of normal in all subjects. By day 28, the activation coefficient of PCC had increased significantly (P = 0.003) and was above the upper limit of normal in 6 of 7 subjects. CONCLUSION: PCC activity is the most sensitive indicator of Biotin status tested to date. In future pregnancy studies, the use of lymphocyte PCC activity data should prove valuable in the assessment of Biotin status.
Nayeli Rodriguezfuentes - One of the best experts on this subject based on the ideXlab platform.
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functional and metabolic implications of Biotin Deficiency for the rat heart
Molecular Genetics and Metabolism, 2008Co-Authors: Antonio Velazquezarellano, Maria De La Luz Hernandezesquivel, Rafael Moreno Sanchez, Daniel Ortegacuellar, Nayeli Rodriguezfuentes, Saul Cano, Alfonso Leondelrio, Karla CarvajalAbstract:The tricarboxylic acid (TCA) cycle is the main ATP provider for the heart. TCA carbons must be replenished by anaplerosis for normal cardiac function. Biotin is cofactor of the anaplerotic enzymes pyruvate and propionyl-CoA carboxylases. Here, we found that in Biotin deficient rats, both carboxylases decreased 90% in adipose tissue, jejunum and spleen, but in heart they conserved about 60% residual activity. We then investigated if under Biotin Deficiency (BtDEF), the heart is able to maintain its function in vivo and in isolated conditions, and during ischemia and reperfusion, where metabolism drastically shifts from oxidative to mainly glycolytic. Neither glucose nor octanoate oxidation were severely affected in BtDEF hearts, as assessed by mechanical performance, oxygen uptake or high-energy metabolite content; however, myocardial hexokinase activity and lactate concentration were reduced in deficient hearts. When challenged by ischemia and reperfusion injury, BtDEF hearts did not suffer more damage than the controls, although they lowered significantly their performance, when changed to ischemic conditions, which may have clinical implications. Post-ischemic increase in ADP/ATP ratio was similar in both groups, but during reperfusion there was higher rhythm perturbation in BtDEF hearts. By being relatively insensitive to Biotin Deficiency, cardiac tissue seems to be able to replenish TCA cycle intermediates and to maintain ATP synthesis.
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Biotin Deficiency affects both synthesis and degradation of pyruvate carboxylase in rat primary hepatocyte cultures
Molecular Genetics and Metabolism, 2007Co-Authors: Nayeli Rodriguezfuentes, Itzel Lopezrosas, Gabriela Romancisneros, Antonio VelazquezarellanoAbstract:Abstract Pyruvate carboxylase (PC) is a Biotin-dependent enzyme that plays a crucial role in gluconeogenesis, lipogenesis, Krebs cycle anaplerosis and amino acid catabolism. Biotin Deficiency reduces its mass besides its activity. Enzyme mass is the result of its cellular turnover, i.e., its rates of synthesis and degradation. We have now investigated, by a pulse and chase approach in cultured primary hepatocytes, the effects of Biotin Deficiency on these rates. Wistar rats were fed a Biotin-deficient diet and the controls were fed the same diet supplemented with Biotin; their Biotin status was monitored measuring lymphocytes propionyl-CoA carboxylase activity and urinary 3-hydroxyisovaleric acid. After 6–7 weeks primary hepatocytes were cultured in Biotin-deficient or complete DMEM. PC activity was determined by measuring the incorporation of 14 C-bicarbonate into acid-non-volatile products, and its mass by streptavidin Western blots. Its synthesis rate was estimated from [ 35 S] methionine incorporation into anti-PC antibody immunoprecipitate. Its degradation rate was calculated from the loss of radioactivity from previously labeled hepatocytes, in a medium containing an excess of non-radioactive methionine. PC synthesis rate in Biotin-deficient hepatocytes was approximately 4.5-fold lower than in the controls, and its degradation rate was 5.1-fold higher. Therefore, the decrement of PC mass during Biotin Deficiency results both from a decrease in its synthesis and an increase in its degradation rates. To our knowledge, this is the first instance where a mammalian enzyme cofactor is necessary to sustain both processes.
