scholarly journals Metabolic persistence of fetal hemoglobin

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1712-1718 ◽  
Author(s):  
JA Little ◽  
NJ Dempsey ◽  
M Tuchman ◽  
GD Ginder
Keyword(s):  
Fatty Acid ◽  
Short Chain Fatty Acid ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Erythroid Cell ◽  
Gene Promoters ◽  
Beta Globin ◽  
Rnase Protection

Hereditary persistence of fetal hemoglobin (HPFH) has typically been ascribed to mutations in the beta-globin gene cluster. Pharmacologic agents, including the short-chain fatty acid butyrate, have been shown to upregulate fetal and embryonic globin gene expression. In this report we investigate the possibility that metabolic derangements characterized by an inability to metabolize another short-chain fatty acid, propionate, could be associated with a persistence of fetal hemoglobin unrelated to alterations in the beta-globin cluster. Embryonic globin gene upregulation in a murine adult erythroid cell culture was shown by RNase protection after induction with three short-chain fatty acids (C2-C5). Chart reviews and measurement of fetal hemoglobin in five patients with abnormalities in propionate (C3) metabolism were undertaken; SSCP/dideoxy fingerprint analysis of the gamma-globin gene promoters was done in three of these five patients. Twelve patients with other metabolic derangements served as controls. Only the four patients with clinically severe abnormalities in propionate metabolism (ages 2 to 11), but without anemia, showed a sustained elevation in fetal hemoglobin (3% to 10%). The level of elevation of fetal hemoglobin in these patients, who lack erythropoietic stress, suggests that propionic acid and/or its metabolites are potent stimulators of fetal hemoglobin expression. Study of this group of patients should allow unique insights into the long-term effects of sustained exposure to elevations of short-chain fatty acid levels.

scholarly journals Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3259-3267 ◽  
Author(s):  
Michael S. Boosalis ◽  
Ram Bandyopadhyay ◽  
Emery H. Bresnick ◽  
Betty S. Pace ◽  
Karyn Van DeMark ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cellular Proliferation ◽  
Short Chain Fatty Acid ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Chain Fatty Acid ◽  
Cellular Growth ◽  
Short Chain ◽  
Hemoglobin F ◽  
Fatty Acid Derivatives

Abstract Current chemotherapeutic and butyrate therapeutics that induce fetal hemoglobin expression generally also suppress erythropoiesis, limiting the production of cells containing fetal hemoglobin (F cells). Recently, selected short-chain fatty acid derivatives (SCFADs) were identified that induce endogenous γ-globin expression in K562 cells and human burst-forming units–erythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3–dependent hematopoietic cell line. In this report, γ-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire β-globin gene locus in a yeast artificial chromosome and in 2 globin promoter-reporter assays. Conditioned media experiments strongly suggest that their proliferative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these compounds induce prolonged expression of the growth-promoting genes c-myb andc-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolonged signal transducer and activator of transcription (STAT)-5 phosphorylation and activation, and c-cisexpression, persisting for more than 120 minutes, whereas with IL-3 alone phosphorylation disappeared within minutes. In contrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21Waf/Cip, which mediates the suppression of cellular growth by butyrate. These findings suggest that the absence of bulk histone hyperacetylation and p21 induction, but prolonged induction of cis, myb, myc, and STAT-5 activation, contribute to the cellular proliferation induced by selected SCFADs.

scholarly journals Stimulation of fetal hemoglobin production by short chain fatty acids

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3227-3235 ◽  
Author(s):  
E Liakopoulou ◽  
CA Blau ◽  
Q Li ◽  
B Josephson ◽  
JA Wolf ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Erythroid Cell ◽  
Gamma Globin ◽  
Carbon Fatty Acid ◽  
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.

scholarly journals Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4640-4648 ◽  
Author(s):  
Betty S. Pace ◽  
Gary L. White ◽  
George J. Dover ◽  
Michael S. Boosalis ◽  
Douglas V. Faller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Short Chain Fatty Acid ◽  
Globin Gene ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Pharmacokinetic Studies ◽  
Fatty Acid Derivatives ◽  
Globin Gene Expression

Orally bioactive compounds that induce γ globin gene expression at tolerable doses are needed for optimal treatment of the β-hemoglobinopathies. Short-chain fatty acids (SCFAs) of 2 to 6 carbons in length induce γ globin expression in animal models, and butyrate, phenylbutyrate, and valproate induce γ globin in human patients. The usefulness of these compounds, however, is limited by requirements for large doses because of their rapid metabolism and their tendency to inhibit cell proliferation, which limits the pool of erythroid progenitors in which γ globin can be induced. Selected short-chain fatty acid derivatives (SCFADs) were recently found to induce γ globin and to stimulate the proliferation of hematopoietic cells in vitro. These SCFADs are now evaluated in vivo in nonanemic transgenic mice containing the human β globin gene locus and in anemic phlebotomized baboons. In mice treated with a SCFAD once daily for 5 days, γ globin mRNA increased 2-fold, reticulocytes increased 3- to 7-fold, and hematocrit levels increased by 27%. Administration of 3 SCFADs in anemic baboons increased F-reticulocytes 2- to 15-fold over baseline and increased total hemoglobin levels by 1 to 2 g/dL per week despite ongoing significant daily phlebotomy. Pharmacokinetic studies demonstrated 90% oral bioavailability of 2 SCFADs, and targeted plasma levels were maintained for several hours after single oral doses equivalent to 10% to 20% of doses required for butyrate. These findings identify SCFADs that stimulate γ globin gene expression and erythropoiesis in vivo, activities that are synergistically beneficial for treatment of the β hemoglobinopathies and useful for the oral treatment of other anemias.

scholarly journals Stimulation of fetal hemoglobin production by short chain fatty acids

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3227-3235 ◽  
Author(s):  
E Liakopoulou ◽  
CA Blau ◽  
Q Li ◽  
B Josephson ◽  
JA Wolf ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Erythroid Cell ◽  
Gamma Globin ◽  
Carbon Fatty Acid ◽  
Chain Fatty Acids

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.

l-Theanine affects intestinal mucosal immunity by regulating short-chain fatty acid metabolism under dietary fiber feeding

2020 ◽  
Vol 11 (9) ◽  
pp. 8369-8379
Author(s):  
Wei Xu ◽  
Ling Lin ◽  
An Liu ◽  
Tuo Zhang ◽  
Sheng Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Dietary Fiber ◽  
Fatty Acid Metabolism ◽  
Mucosal Immunity ◽  
Cholesterol Synthesis ◽  
Short Chain Fatty Acid ◽  
Acid Metabolism ◽  
Chain Fatty Acid ◽  
Short Chain

LTA regulates SCFA metabolism and improves intestinal mucosal immunity by improving cholesterol synthesis in the liver and inhibiting gluconeogenesis in the colon.

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