title: Stimulation of fetal hemoglobin production by short chain fatty acids.
abstract: Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-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 gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta 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 gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta 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 gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma 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 gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.
authors.affiliation: Department of Medicine, University of Washington, Seattle.
authors.forename: E
authors.initials: E
authors.lastname: Liakopoulou
authors.forename: C A
authors.initials: CA
authors.lastname: Blau
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Josephson
authors.forename: J A
authors.initials: JA
authors.lastname: Wolf
authors.forename: B
authors.initials: B
authors.lastname: Fournarakis
authors.forename: V
authors.initials: V
authors.lastname: Raisys
authors.forename: G
authors.initials: G
authors.lastname: Dover
authors.forename: T
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: G
authors.initials: G
authors.lastname: Stamatoyannopoulos
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002478:Cells, Cultured; D004827:Epilepsy / Q000188:drug therapy; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D005232:Fatty Acids, Volatile / Q000737:chemistry / Q000494:pharmacology*; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006453:Hemoglobinopathies / Q000628:therapy; D006801:Humans; D010215:Papio; D010421:Pentanoic Acids / Q000494:pharmacology; D011422:Propionates / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012156:Reticulocytes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D002087:Butyrates; D005232:Fatty Acids, Volatile; D010421:Pentanoic Acids; D011422:Propionates; D012333:RNA, Messenger; D020148:Butyric Acid; D004921:Erythropoietin; D014635:Valproic Acid; D005914:Globins; D005319:Fetal Hemoglobin; C514135:sodium propionate; C038780:n-pentanoic acid; C029658:propionic acid