Fetal hemoglobin induction by acetate, a product of butyrate catabolism

George Stamatoyannopoulos, C. Anthony Blau, Betty Nakamoto, Betty Josephson, Qiliang Li, Effie Liakopoulou, Betty Pace, Thalia Papayannopoulou, Saul W. Brusilow, George J Dover

Research output: Contribution to journalArticle

Abstract

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates γ-globin synthesis is unknown. In the course of butyrate catabolism, β oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in γ- globin protein and γ mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of γ/γ + β mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-γ monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in γ-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of γ-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb μ locus control region (μLCR) cassette linked to a 3.3-kb (A)γ gene displayed a near twofold increase in γ mRNA during a 10- day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of γ- globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

Original languageEnglish (US)
Pages (from-to)3198-3204
Number of pages7
JournalBlood
Volume84
Issue number9
StatePublished - Nov 1 1994
Externally publishedYes

Fingerprint

Fetal Hemoglobin
Butyrates
Acetates
Erythroid Precursor Cells
Globins
Sodium Acetate
Papio
Reticulocytes
Sickle Cell Anemia
Fetal Blood
Messenger RNA
Primates
Transgenic Mice
Blood
Bearings (structural)
Fatty Acids
Carbon
Locus Control Region
Molecules
Intravenous Infusions

ASJC Scopus subject areas

  • Hematology

Cite this

Stamatoyannopoulos, G., Blau, C. A., Nakamoto, B., Josephson, B., Li, Q., Liakopoulou, E., ... Dover, G. J. (1994). Fetal hemoglobin induction by acetate, a product of butyrate catabolism. Blood, 84(9), 3198-3204.

Fetal hemoglobin induction by acetate, a product of butyrate catabolism. / Stamatoyannopoulos, George; Blau, C. Anthony; Nakamoto, Betty; Josephson, Betty; Li, Qiliang; Liakopoulou, Effie; Pace, Betty; Papayannopoulou, Thalia; Brusilow, Saul W.; Dover, George J.

In: Blood, Vol. 84, No. 9, 01.11.1994, p. 3198-3204.

Research output: Contribution to journalArticle

Stamatoyannopoulos, G, Blau, CA, Nakamoto, B, Josephson, B, Li, Q, Liakopoulou, E, Pace, B, Papayannopoulou, T, Brusilow, SW & Dover, GJ 1994, 'Fetal hemoglobin induction by acetate, a product of butyrate catabolism', Blood, vol. 84, no. 9, pp. 3198-3204.
Stamatoyannopoulos G, Blau CA, Nakamoto B, Josephson B, Li Q, Liakopoulou E et al. Fetal hemoglobin induction by acetate, a product of butyrate catabolism. Blood. 1994 Nov 1;84(9):3198-3204.
Stamatoyannopoulos, George ; Blau, C. Anthony ; Nakamoto, Betty ; Josephson, Betty ; Li, Qiliang ; Liakopoulou, Effie ; Pace, Betty ; Papayannopoulou, Thalia ; Brusilow, Saul W. ; Dover, George J. / Fetal hemoglobin induction by acetate, a product of butyrate catabolism. In: Blood. 1994 ; Vol. 84, No. 9. pp. 3198-3204.
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abstract = "Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates γ-globin synthesis is unknown. In the course of butyrate catabolism, β oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in γ- globin protein and γ mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of γ/γ + β mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-γ monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in γ-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of γ-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb μ locus control region (μLCR) cassette linked to a 3.3-kb (A)γ gene displayed a near twofold increase in γ mRNA during a 10- day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of γ- globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30{\%}. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.",
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N2 - Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates γ-globin synthesis is unknown. In the course of butyrate catabolism, β oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in γ- globin protein and γ mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of γ/γ + β mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-γ monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in γ-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of γ-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb μ locus control region (μLCR) cassette linked to a 3.3-kb (A)γ gene displayed a near twofold increase in γ mRNA during a 10- day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of γ- globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

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