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Title: Fatty acid uptake in normal human myocardium

Abstract

Fatty acid binding protein has been found in rat aortic endothelial cell membrane. It has been identified to be a 40-kDa protein that corresponds to a 40-kDa fatty acid binding protein with high affinity for a variety of long chain fatty acids isolated from rat heart myocytes. It is proposed that this endothelial membrane fatty acid binding protein might mediate the myocardial uptake of fatty acids. For evaluation of this hypothesis in vivo, influx kinetics of tracer-labeled fatty acids was examined in 15 normal subjects by scintigraphic techniques. Variation of the plasma fatty acid concentration and plasma perfusion rate has been achieved by modulation of nutrition state and exercise conditions. The clinical results suggest that the myocardial fatty acid influx rate is saturable by increasing fatty acid plasma concentration as well as by increasing plasma flow. For analysis of these data, functional relations describing fatty acid transport from plasma into myocardial tissue in the presence and absence of an unstirred layer were developed. The fitting of these relations to experimental data indicate that the free fatty acid influx into myocardial tissue reveals the criteria of a reaction on a capillary surface in the vicinity of flowing plasma but not ofmore » a reaction in extravascular space or in an unstirred layer and that the fatty acid influx into normal myocardium is a saturable process that is characterized by the quantity corresponding to the Michaelis-Menten constant, Km, and the maximal velocity, Vmax, 0.24 {plus minus} 0.024 mumol/g and 0.37 {plus minus} 0.013 mumol/g(g.min), respectively. These data are compatible with a nondiffusional uptake process mediated by the initial interaction of fatty acids with the 40-kDa membrane fatty acid binding protein of cardiac endothelial cells.« less

Authors:
; ; ; ; ; ; ; ;  [1]
  1. (University of Bochum (West Germany))
Publication Date:
OSTI Identifier:
5228784
Resource Type:
Journal Article
Resource Relation:
Journal Name: Circulation Research (An Official Journal of the American Heart Association); (United States); Journal Volume: 69:3
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CARBOXYLIC ACIDS; METABOLISM; MYOCARDIUM; PROTEINS; BIOSYNTHESIS; AORTA; CELL MEMBRANES; DYNAMIC FUNCTION STUDIES; ENDOTHELIUM; EXERCISE; MAN; SCINTISCANNING; THALLIUM ISOTOPES; ANIMAL TISSUES; ANIMALS; ARTERIES; BLOOD VESSELS; BODY; CARDIOVASCULAR SYSTEM; CELL CONSTITUENTS; COUNTING TECHNIQUES; DIAGNOSTIC TECHNIQUES; HEART; ISOTOPES; MAMMALS; MEMBRANES; MUSCLES; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANS; PRIMATES; RADIOISOTOPE SCANNING; SYNTHESIS; TISSUES; VERTEBRATES; 550601* - Medicine- Unsealed Radionuclides in Diagnostics

Citation Formats

Vyska, K., Meyer, W., Stremmel, W., Notohamiprodjo, G., Minami, K., Machulla, H.J., Gleichmann, U., Meyer, H., and Koerfer, R. Fatty acid uptake in normal human myocardium. United States: N. p., 1991. Web. doi:10.1161/01.RES.69.3.857.
Vyska, K., Meyer, W., Stremmel, W., Notohamiprodjo, G., Minami, K., Machulla, H.J., Gleichmann, U., Meyer, H., & Koerfer, R. Fatty acid uptake in normal human myocardium. United States. doi:10.1161/01.RES.69.3.857.
Vyska, K., Meyer, W., Stremmel, W., Notohamiprodjo, G., Minami, K., Machulla, H.J., Gleichmann, U., Meyer, H., and Koerfer, R. 1991. "Fatty acid uptake in normal human myocardium". United States. doi:10.1161/01.RES.69.3.857.
@article{osti_5228784,
title = {Fatty acid uptake in normal human myocardium},
author = {Vyska, K. and Meyer, W. and Stremmel, W. and Notohamiprodjo, G. and Minami, K. and Machulla, H.J. and Gleichmann, U. and Meyer, H. and Koerfer, R.},
abstractNote = {Fatty acid binding protein has been found in rat aortic endothelial cell membrane. It has been identified to be a 40-kDa protein that corresponds to a 40-kDa fatty acid binding protein with high affinity for a variety of long chain fatty acids isolated from rat heart myocytes. It is proposed that this endothelial membrane fatty acid binding protein might mediate the myocardial uptake of fatty acids. For evaluation of this hypothesis in vivo, influx kinetics of tracer-labeled fatty acids was examined in 15 normal subjects by scintigraphic techniques. Variation of the plasma fatty acid concentration and plasma perfusion rate has been achieved by modulation of nutrition state and exercise conditions. The clinical results suggest that the myocardial fatty acid influx rate is saturable by increasing fatty acid plasma concentration as well as by increasing plasma flow. For analysis of these data, functional relations describing fatty acid transport from plasma into myocardial tissue in the presence and absence of an unstirred layer were developed. The fitting of these relations to experimental data indicate that the free fatty acid influx into myocardial tissue reveals the criteria of a reaction on a capillary surface in the vicinity of flowing plasma but not of a reaction in extravascular space or in an unstirred layer and that the fatty acid influx into normal myocardium is a saturable process that is characterized by the quantity corresponding to the Michaelis-Menten constant, Km, and the maximal velocity, Vmax, 0.24 {plus minus} 0.024 mumol/g and 0.37 {plus minus} 0.013 mumol/g(g.min), respectively. These data are compatible with a nondiffusional uptake process mediated by the initial interaction of fatty acids with the 40-kDa membrane fatty acid binding protein of cardiac endothelial cells.},
doi = {10.1161/01.RES.69.3.857},
journal = {Circulation Research (An Official Journal of the American Heart Association); (United States)},
number = ,
volume = 69:3,
place = {United States},
year = 1991,
month = 9
}
  • Myocardial blood flow (MBF) is heterogeneously distributed in normal and ischemic myocardium (myoc). Methylated iodinated fatty acids, like 15-(p-I-125-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPPA) can be used to study fatty acid metabolism with SPECT. We studied the relationship between DMIPPA uptake and MBF. In 10 open-chest dogs, ischemica was induced in the LAD coronary artery by an extra-corporal bypass system. MBF was measured with Sc-46 labeled microspheres. Fourty min. after DMIPPA iv. (34{plus_minus}4 MBq), hearts were excised and left ventricles were cut into 120 pieces, weighed and radioactivities counted. MBF and DMIPPA uptake were determined by counting in normal and ischemic myoc. Heterogeneitymore » is expressed as the coefficient of variation (CV) and agreement as the CV of the DMIPPA uptake to MBF ratio. A control study, normal flow in LAD, in 4 dogs revealed no differences in MBF or DMIPPA uptake between the cannulated versus native perfused myoc. We conclude the DMIPPA detects ischemia, in which it shows a different relation with MBF compared to normal myoc. DMIPPA is less heterogeneously distributed than MBF and agreement between MFB and DMIPPA uptake decreases during ischemia.« less
  • No abstract prepared.
  • The uptake of metabolic substrates by the heart is dependent, in part, on the concentration of alternative substrates in the blood. To determine the effect of increasing blood concentrations of lactate (L) on the myocardial concentration of fatty acid, studies were performed in 5 closed chest, anesthetized dogs. A modified fatty acid, 14-p-(I-123)iodophenyl beta methyl tetradecanoic acid (BMFA), which is taken up by the cell but does not undergo beta oxidation, was compared to Tl-201, a marker of perfusion. Two sets of measurements were made: (a) basal Tl and BMFA; followed by infusion of L and (b) reinjection of Tlmore » and BMFA. Sequential 1 minute images were collected for 32 minutes after injection of each tracer, corrected for background activity, and analyzed to produce time/activity curves from the myocardium. A ratio of BMFA/Tl at 10 minutes after injection was calculated. BMFA/Tl was 1.33 +- 31 (mean +- SD) pre L and decreased to 0.72 +- 12 post L. The Tl values before and after L remained essentially unchanged. In conclusion, there is a discordance between myocardial blood flow (Tl) and BMFA distribution following L infusion. The change in BMFA/Tl ratio suggests that elevated L decreases BMFA concentration in the heart.« less
  • Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) has been prepared as a new terminal iodophenyl-substituted fatty acid containing dimethyl-branching at the beta position. For the synthesis of this new agent, chain homologation was accomplished by fabrication of a 2,5-disubstituted thiophene by successive Friedel-Crafts acylation and Wolff-Kishner reduction reactions, followed by thiophene ring opening. The dimethyl-branching was introduced using the monomethyl ester of dimethylglutaryl chloride. Radioiodination of the 15-phenyl-3,3-dimethylpentadecanoic acid substrate in the para position then gave DMIPP. Iodine-125-labeled DMIPP showed rapid, high myocardial uptake (min, mean % injected dose/g) in fasted rats (5, 4.67; 30, 5.06; 60, 4.79; 120, 4.37), and also exhibitedmore » good heart:blood ratios (min, heart:blood: 5, 3:1; 30, 12:1; 60, 12:1; 120, 13:1). To further evaluate the effects of dimethyl-branching, the biodistribution properties of DMIPP were compared with the 3-monomethyl-branched (15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid; BMIPP) and the unbranched (15-(p-iodophenyl)pentadecanoic acid; IPP) analogs. A triple-labeled (/sup 123/I)DMIPP/(/sup 131/I)BMIPP/(/sup 125/I)IPP mixture was administered to groups of fasted rats. These results confirmed the greater myocardial retention and higher heart:blood ratios observed with DMIPP in comparison with both the 3-monomethyl-(BMIPP) and unbranched (IPP) analogs. These data suggest that (/sup 123/3I)DMIPP is an excellent candidate for clinical evaluation of regional energy substrates (fatty acid) uptake.« less
  • Highlights: •Roles of FATP2 in fatty acid transport/activation contribute to lipid homeostasis. •Use of 13C- and D-labeled fatty acids provide novel insights into FATP2 function. •FATP2-dependent trafficking of FA into phospholipids results in distinctive profiles. •FATP2 functions in the transport and activation pathways for exogenous fatty acids. -- Abstract: In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4,more » for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4 h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of FATP2 resulted in increases in all four classes of phospholipid, indicating little selectivity. In the case of C22:6, there were significant increases of this exogenous fatty acids being trafficking into PC and PI. Collectively, these data support the conclusion that FATP2 has a dual function in the pathways linking the transport and activation of exogenous fatty acids. We discuss the differential roles of FATP2 and its role in both fatty acid transport and fatty acid activation in the context of lipid homeostasis.« less