Stimulation of fetal hemoglobin production by short chain fatty acids

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of γ-globin synthesis. To test whether other short- chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces γ-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the γ/γ + β mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced γ- globin expression (as measured by increase in γ-positive erythroblasts and γ/γ + β mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of γ-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of γ globin in culture as compared with six-to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of γ-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces γ- globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of γ-globin inducibility and may be of therapeutic relevance to the β-chain hemoglobinopathies.