scholarly journals Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

2021 ◽  
Author(s):  
Tiago Beites ◽  
Robert S Jansen ◽  
Ruojun Wang ◽  
Adrian Jinich ◽  
Kyu Y Rhee ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Acid Metabolism ◽  
Dehydrogenase Deficiency ◽  
Long Chain Fatty Acids ◽  
Human Pathogen ◽  
Antitubercular Drugs ◽  
Acyl Coa Dehydrogenases

The human pathogen Mycobacterium tuberculosis (Mtb) devotes a significant fraction of its genome to fatty acid metabolism. Although Mtb depends on host fatty acids as a carbon source, fatty acid β-oxidation is mediated by genetically redundant enzymes, which has hampered the development of antitubercular drugs targeting this metabolic pathway. Here, we identify rv0338c, referred to as etfDMtb, to encode a membrane dehydrogenase essential for fatty acid β-oxidation in Mtb. An etfD deletion mutant (ΔetfD) was incapable of growing on fatty acids in vitro, with long-chain fatty acids being bactericidal, and failed to grow and survive in mice. The ΔetfD metabolome revealed a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs). In many organisms, including humans, ACADs are functionally dependent on an electron transfer flavoprotein (ETF) and cognate dehydrogenase. Immunoprecipitation identified EtfD in complex with FixA (EtfBMtb). FixA (EtfBMtb) and FixB (EtfAMtb) are homologous to the human ETF subunits. Our results demonstrate that EtfBAMtb constitutes Mtb's ETF, while EtfDMtb, although not homologous to human EtfD, functions as the dehydrogenase. These findings identify Mtb's fatty acid β-oxidation as a novel potential target for TB drug development.

scholarly journals Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tiago Beites ◽  
Robert S. Jansen ◽  
Ruojun Wang ◽  
Adrian Jinich ◽  
Kyu Y. Rhee ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Deletion Mutant ◽  
Dehydrogenase Deficiency ◽  
Long Chain Fatty Acids ◽  
Human Pathogen ◽  
Antitubercular Drugs ◽  
Acyl Coa Dehydrogenases ◽  
Long Chain

AbstractThe human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant’s metabolome reveals a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit β and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.

scholarly journals Interactions of insulin, corticosterone and prolactin in promoting milk-fat synthesis by mammary explants from pregnant rabbits

1972 ◽  
Vol 129 (4) ◽  
pp. 929-935 ◽  
Author(s):  
Isabel A. Forsyth ◽  
Christopher R. Strong ◽  
Raymond Dils
Keyword(s):  
Fatty Acids ◽  
Mammary Gland ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Long Chain Fatty Acids ◽  
Medium Chain ◽  
Long Chain ◽  
Chain Fatty Acids

1. The rate of fatty acid synthesis by mammary explants from rabbits pregnant for 16 days or from rabbits pseudopregnant for 11 days was stimulated up to 15-fold by culturing for 2–4 days with prolactin. This treatment initiated the predominant synthesis of C8:0 and C10:0 fatty acids, which are characteristic of rabbit milk. 2. Inclusion of insulin in the culture medium increased the rate of synthesis of these medium-chain fatty acids. By contrast the inclusion of corticosterone led to the predominant synthesis of long-chain fatty acids. When explants were cultured for 2–4 days with insulin, corticosterone and prolactin, the rate of fatty acid synthesis increased up to 42-fold, but both medium- and long-chain fatty acids were synthesized. 3. These results show that the stimulus to mammary-gland lipogenesis and the initiation of synthesis of medium-chain fatty acids observed between days 16 and 23 of pregnancy in the rabbit can be simulated in vitro by prolactin alone. 4. When mammary explants from rabbits pregnant for 23 days were cultured for 2 days with insulin, corticosterone and prolactin, the rate of fatty acid synthesis increased fivefold, but there was a preferential synthesis of long-chain fatty acids. Culture with prolactin alone had little effect on the rate or pattern of fatty acids synthesized. 5. The results are compared with findings in vivo on the control of lipogenesis in the rabbit mammary gland, and are contrasted with the known effects of hormones in vitro on the mammary gland of the mid-pregnant mouse.

scholarly journals The Oxidation of Long-Chain Fatty Acids by the Formed Elements of Human Blood

Blood ◽  
1966 ◽  
Vol 27 (1) ◽  
pp. 57-64 ◽  
Author(s):  
ARNOLD ROSENZWEIG ◽  
PETER WAYS
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Human Blood ◽  
Potassium Salt ◽  
Surrounding Medium ◽  
Human Erythrocytes ◽  
Molar Ratio ◽  
Long Chain Fatty Acids ◽  
Long Chain

Abstract 1. In vitro, human erythrocytes free of contaminating white cells and platelets do not oxidize fatty acid in the surrounding medium, either bound to albumin or supplied in buffer as the potassium salt. These results are not influenced by glucose deficiency. 2. White cells and platelets are both capable of oxidizing fatty acid from the surrounding medium—supplied either as the potassium salt in buffer or bound to albumin. Increasing the albumin/fatty acid molar ratio results in a decrease in the quantity of fatty acid oxidized. The amount of fatty acid oxidized is greater if glucose is not added to the medium.

scholarly journals Differential Effects of Fatty Acid Saturation and Chain Length on NASH in Juvenile Iberian Pigs

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 682-682 ◽  
Author(s):  
Kayla Dillard ◽  
Morgan Coffin ◽  
Gabriella Hernandez ◽  
Victoria Smith ◽  
Catherine Johnson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Body Weight ◽  
Fatty Acid ◽  
Liver Injury ◽  
Olive Oil ◽  
Coconut Oil ◽  
Long Chain Fatty Acids ◽  
Medium Chain ◽  
Long Chain ◽  
Chain Fatty Acids

Abstract Objectives Non-alcoholic fatty liver disease (NAFLD) represents the major cause of pediatric chronic liver pathology in the United States. The objective of this study was to compare the relative effect of inclusion of isocaloric amounts of saturated medium-chain fatty acids (hydrogenated coconut oil), saturated long-chain fatty acids (lard) and unsaturated long-chain fatty acids (olive oil) on endpoints of NAFLD and insulin resistance. Methods Thirty-eight 15-d-old Iberian pigs were fed 1 of 4 diets containing (g/kg body weight × d) 1) control (CON; n = 8): 0 g fructose, 10.5 g fat, and 187 kcal metabolizable energy (ME), 2) lard (LAR; n = 10): 21.6 g fructose, 17.1 g fat (100% lard) and 299 kcal ME, 3) hydrogenated coconut oil (COCO; n = 10): 21.6 g fructose, 16.9 g fat (42.5% lard and 57.5% coconut oil) and 299 kcal ME, and 4) olive oil (OLV, n = 10): 21.6 g fructose, 17.1 g fat (43.5% lard and 56.5% olive oil) and 299 kcal ME, for 9 consecutive weeks. Body weight was recorded every 3 d. Serum markers of liver injury and dyslipidemia were measured on d 60 at 2 h post feeding, with all other serum measures assessed on d 70. Liver tissue was collected on d 70 for histology, triacylglyceride (TG) quantification, and metabolomics analysis. Results Tissue histology indicated the presence of steatosis in LAR, COCO and OLV compared with CON (P ≤ 0.001), with a further increase in in non-alcoholic steatohepatitis (NASH) in OLV and COCO compared with LAR (P ≤ 0.01). Alanine and aspartate aminotransferases were higher in COCO and OLV (P ≤ 0.01) than CON. All treatment groups had lower liver concentrations of methyl donor's choline and betaine versus CON, while bile acids were differentially changed (P ≤ 0.05). COCO had higher levels of TGs with less carbons (Total carbons < 52) than all other groups (P ≤ 0.05). Several long-chain acylcarnitines involved in fat oxidation were higher in OLV versus all other groups (P ≤ 0.05). Conclusions Inclusion of fats enriched in medium-chain saturated and long-chain unsaturated fatty acids in a high-fructose high-fat diet increased liver injury, compared with fats with a long-chain saturated fatty acid profile. Further research is required to investigate the mechanisms causing this difference in physiological response to these dietary fat sources. Funding Sources ARI, AcornSeekers.

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