FETAL HEMOGLOBIN INDUCTION BY ACETATE, A PRODUCT OF BUTYRATE CATABOLISM

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of eryth roid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes result s in the formation of two acetate molecules from each molecule of buty rate. Studies were performed to determine whether acetate itself induc es HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures fro m normal persons, and individuals with sickle cell disease and umbilic al-cord blood, dose-dependent increases in gamma-globin protein and ga mma 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 gamma/gamma + beta mRNA increased t wofold to fivefold in response to acetate, whereas the percentage of B FU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) in creased approximately twofold. Acetate-induced increases in gamma-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 b ecause of a higher baseline of gamma-chain production. The effect of a cetate on HbF induction in vivo was evaluated using transgenic mouse a nd primate models. A transgenic mouse bearing a 2.5-kb mu locus contro l region (mu LCR) cassette linked to a 3.3-kb (A) gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sod ium 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 intraveno us infusion, also resulted in the stimulation of gamma-globin synthesi s, with the percentage of HbF-containing reticulocytes (F reticulocyte s) 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 sug gest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of H6F in vivo. (C) 1994 by The A merican Society of Hematology.