Biotin Supplementation Increases Expression of Genes Encoding Interferon-γ, Interleukin-1β, and 3-Methylcrotonyl-CoA Carboxylase, and Decreases Expression of the Gene Encoding Interleukin-4 in Human Peripheral Blood Mononuclear Cells

Wiedmann, Silke; Eudy, James D.; Zempleni, Janos

doi:10.1093/jn/133.3.716

Cited by 41 publications

(33 citation statements)

References 23 publications

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“…This metabolic activation of procarcinogens is a key factor in carcinogenesis of the human prostate [64,65], breast [66], and uterus [67]. Collectively, effects of biotin on gene expression [5,14] and cell signaling [11,12] need to be considered when establishing Tolerable Upper Intake Levels for biotin [40].…”

Section: Discussionmentioning

confidence: 99%

“…Second, histones (DNA-binding proteins) contain covalently bound biotin [2]; biotinylation of histones might play a role in gene silencing [3], cell proliferation [2,4], and DNA repair or apoptosis [3]. Third, biotin affects gene expression at both the transcriptional [5][6][7] and the posttranscriptional level [6,8,9]. Numerous cell signals have been identified that mediate effects of biotin on gene expression: biotinyl-AMP [10], transcription factors such as NF-κB [11], Sp1 and Sp3 [12], and biotinylation of histones [13].…”

Section: Introductionmentioning

confidence: 99%

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Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response

Griffin

Rodriguez-Melendez

Dode

et al. 2006

The Journal of Nutritional Biochemistry

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Protein folding in the endoplasmic reticulum (ER) depends on Ca 2+ ; uptake of Ca 2+ into the ER is mediated by SERCA3. The 5′-flanking region of the SERCA3 gene (ATP2A3) contains numerous binding sites for the transcription factors Sp1 and Sp3. Biotin affects the nuclear abundance of Sp1 and Sp3, which may act as transcriptional activators or repressors. Here we determined whether biotin affects the expression of the SERCA3 gene and, thus, protein folding in human lymphoid cells. Jurkat cells were cultured in media containing 0.025 nmol/L biotin (denoted "deficient") or 10 nmol/L biotin ("supplemented"). The transcriptional activity of the full-length human SERCA3 promoter was 50% lower in biotin-supplemented cells compared to biotin-deficient cells. Biotin-dependent repressors bind to elements located 731 to 1312 basepairs upstream from the transcription start site in the SERCA3 gene. The following lines of evidence suggest that low expression of SERCA3 in biotinsupplemented cells impaired folding of secretory proteins in the ER, triggering Unfolded Protein Response: (i) sequestration of Ca 2+ in the ER decreased by 14-24% in response to biotin supplementation; (ii) secretion of interleukin-2 into the extracellular space decreased by 75% in response to biotin supplementation; (iii) the nuclear abundance of stress-induced transcription factors increased in response to biotin supplementation; and (iv) the abundance of stress-related proteins such UBE1, GADD153, XBP1, and phosphorylated eIF2α increased in response to biotin supplementation. Collectively, this study suggests that supplements containing pharmacological doses of biotin may cause cell stress by impairing protein folding in the ER.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response

Griffin

Rodriguez-Melendez

Dode

et al. 2006

The Journal of Nutritional Biochemistry

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“…The abundance of mRNA coding for flavokinase and FAD synthetase was quantified using RT-PCR as described [16,17]; mRNA coding for glyceraldehyde-3-phosphate dehydrogenase was used as a control. The following gene-specific primers were used: 5′-AGA TGG TGG TGA GCA TAG GA-3′ and 5′-CCA CTG CAC TTG GCC TTA AT-3′ for flavokinase; 5′-GTT TGC CGA GTC TCA GTT GT-3′ and 5′-AAT GCC TGG GAA GAG GTA GA-3′ for FAD synthetase; and 5′-ACC ACA GTC CAT GCC ATC AC-3′ and 5′-TCC ACC ACC CTG TTG CTG TA-3′ for glyceraldehyde-3-phosphate dehydrogenase.…”

Section: Reverse Transcriptase Polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

“…The following gene-specific primers were used: 5′-AGA TGG TGG TGA GCA TAG GA-3′ and 5′-CCA CTG CAC TTG GCC TTA AT-3′ for flavokinase; 5′-GTT TGC CGA GTC TCA GTT GT-3′ and 5′-AAT GCC TGG GAA GAG GTA GA-3′ for FAD synthetase; and 5′-ACC ACA GTC CAT GCC ATC AC-3′ and 5′-TCC ACC ACC CTG TTG CTG TA-3′ for glyceraldehyde-3-phosphate dehydrogenase. Only values from within the exponential phase of PCR amplification were considered for analysis by gel densitometry [17].…”

Section: Reverse Transcriptase Polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

HepG2 cells develop signs of riboflavin deficiency within 4 days of culture in riboflavin-deficient medium

Werner

Manthey

Griffin

et al. 2005

The Journal of Nutritional Biochemistry

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Flavin mononucleotide and flavin adenine dinucleotide are essential coenzymes in redox reactions. For example, flavin adenine dinucleotide is a coenzyme for both glutathione reductase and enzymes that mediate the oxidative folding of secretory proteins. Here we investigated short-term effects of moderately riboflavin-deficient culture medium on flavin-related responses in HepG2 hepatocarcinoma cells. Cells were cultured in riboflavin-deficient (3.1 nmol/L) medium for up to six days; controls were cultured in riboflavin-sufficient (532 nmol/L) medium. The activity of glutathione reductase decreased by 98% within four days of riboflavin-deficient culture. Transport rates of riboflavin increased in response to riboflavin depletion, whereas expression of enzymes mediating flavocoenzyme synthesis (flavokinase and flavin adenine dinucleotide synthetase) decreased in response to depletion. The oxidative folding and synthesis of plasminogen and apolipoprotein B-100, respectively, was impaired within four days of culture in riboflavin-deficient medium; this is consistent with impaired processing of secretory proteins in riboflavin-deficient cells. Riboflavin depletion was associated with increased DNA-binding activities of transcription factors with affinity for endoplasmic reticulum stress elements and NF-κB consensus elements, suggesting cell stress. Moreover, the abundance of the stress-induced protein GADD153 was greater in riboflavin-deficient cells compared with controls. Riboflavin deficiency was associated with decreased rates of cell proliferation caused by arrest in G1 phase of the cell cycle. These studies are consistent with the hypothesis that HepG2 cells have a great demand for riboflavin, and that cell stress develops rapidly if riboflavin supply is marginally low.

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“…Supplementation of biotin in cultured human cells modulates the expression of genes related to cell growth and immune response. [4][5][6][7] Furthermore, mRNA of hepatic glucokinase (GCK), an initial glycolytic enzyme, is increased by biotin administration in fasting or streptozotocin (STZ)-induced diabetic rats; [8][9][10][11] in contrast, the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PCK1), mRNA inversely decreases. 12) Recently, biotinyl histones have been discovered in biotin-supplemented cultured human cells, and this novel histone modification is thought to repress or enhance classical histone modifications, such as phosphorylation, acetylation and methylation, and to bring about epigenetic alterations in chromatin.…”

mentioning

confidence: 99%

Effect of Biotin Treatment on Hepatic Gene Expression in Streptozotocin-Induced Diabetic Rats

Sugita

Shirakawa

Sugimoto

et al. 2008

Bioscience, Biotechnology, and Biochemistry

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Biotin Supplementation Increases Expression of Genes Encoding Interferon-γ, Interleukin-1β, and 3-Methylcrotonyl-CoA Carboxylase, and Decreases Expression of the Gene Encoding Interleukin-4 in Human Peripheral Blood Mononuclear Cells

Abstract: Stimulation of immune cells by antigens triggers changes in the transcription

Cited by 41 publications

References 23 publications

Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response

Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response

HepG2 cells develop signs of riboflavin deficiency within 4 days of culture in riboflavin-deficient medium

Effect of Biotin Treatment on Hepatic Gene Expression in Streptozotocin-Induced Diabetic Rats

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