The capillary transport system for free fatty acids in the heart.

Goresky, Carl A.; Stremmel, Wolfgang; Rose, Colin P.; Guirguis, S; Schwab, Andreas; Diede, Hans Erich; Ibrahim, Emad

doi:10.1161/01.res.74.6.1015

Cited by 45 publications

(17 citation statements)

References 44 publications

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“…Given that fatty acid is the prime substrate for the heart and that its transport is at least partially mediated by a facilitated transport (8,27,51,58), it makes sense for a transporter protein to be expressed in proportion to the need for substrate locally. The correlation principle (impedance-matching idea) is supported by the observations of Caldwell et al (23) that regional fatty acid transport capacity in the hearts of dogs during exercise on a treadmill ramp is proportional to the regional flows.…”

Section: Discussionmentioning

confidence: 99%

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy

Yipintsoi

Kroll

Bassingthwaighte

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Yipintsoi T, Kroll K, Bassingthwaighte JB. Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy. Am J Physiol Heart Circ Physiol 310: H351-H364, 2016. First published November 20, 2015 doi:10.1152/ajpheart.00632.2015.-Regional myocardial blood flows are markedly heterogeneous. Fractal analysis shows strong near-neighbor correlation. In experiments to distinguish control by vascular anatomy vs. local vasomotion, coronary flows were increased in open-chest dogs by stimulating myocardial metabolism (catecholamines ϩ atropine) with and without adenosine. During control states mean left ventricular (LV) myocardial blood flows (microspheres) were 0.5-1 ml·g Ϫ1 ·min Ϫ1 and increased to 2-3 ml·g Ϫ1 ·min Ϫ1 with catecholamine infusion and to ϳ4 ml·g Ϫ1 ·min Ϫ1with adenosine (Ado). Flow heterogeneity was similar in all states: relative dispersion (RD ϭ SD/mean) was ϳ25%, using LV pieces 0.1-0.2% of total. During catecholamine infusion local flows increased in proportion to the mean flows in 45% of the LV, "tracking" closely (increased proportionately to mean flow), while ϳ40% trended toward the mean. Near-neighbor regional flows remained strongly spatially correlated, with fractal dimension D near 1.2 (Hurst coefficient 0.8). The spatial patterns remain similar at varied levels of metabolic stimulation inferring metabolic dominance. In contrast, adenosine vasodilation increased flows eightfold times control while destroying correlation with the control state. The Ado-induced spatial patterns differed from control but were self-consistent, inferring that with full vasodilation the relaxed arterial anatomy dominates the distribution. We conclude that vascular anatomy governs flow distributions during adenosine vasodilation but that metabolic vasoregulation dominates in normal physiological states. THERE IS MARKED HETEROGENEITY of regional blood flows in the heart. The SDs of the distributions of the flows divided by the mean flow, the relative dispersion (RD) are 20 -30% of the mean. (RD is the coefficient of variation.) Myocardial perfusion heterogeneity was recognized in early studies of myocardial regional blood flows by investigators using microspheres in anesthetized dogs (20, 56), in isolated blood-perfused dog hearts (6, 64), and in awake, resting, or exercising animals (22,23,35). In awake baboons, King et al. (35), using 15-m carbonized microspheres in pieces weighing ϳ0.6% of the total mass of the heart, found that the RDs for the left ventricular (LV) flow distributions were 26 Ϯ 7%. This variation is real, since only a small component of it is due to methodology: estimates using the deposited tracer "molecular microsphere" iodinated desmethyl imipramine showed method variation of 2-3% while the microsphere method variation is 5-8% (10), affirming the earlier estimates of method error appropriate to the numbers of spheres per piece and the counting statistics (1,6,20,25,35,48,42). It is a truism that the finer the spatial resolution of the observations, the more heterogen...

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Section: Discussionmentioning

confidence: 99%

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy

Yipintsoi

Kroll

Bassingthwaighte

2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…4, A-C) emphasizes the role of palmitate diffusion bound to L-FABP as a determinant of its extraction. Uptake and intracellular trafficking of fatty acids has been studied in hepatocyte suspensions (1,8) and perfused rat liver (17,18,26,39). In those studies, it is generally acknowledged that the transmembrane flux of long-chain fatty acids occurs by diffusion and by a transmembrane transporter (i.e., FABP).…”

Section: Discussionmentioning

confidence: 99%

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Hung

Burczynski

Chang

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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kinetics of [ 3 H]palmitate and its low-molecular-weight metabolites in perfused rat livers were studied using the multiple-indicator dilution technique, a selective assay for [ 3 H]palmitate and its low-molecular-weight metabolites, and several physiologically based pharmacokinetic models. The level of liver fatty acid binding protein (L-FABP), other intrahepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [ 3 H]palmitate and metabolites were measured in four experimental groups of rats: 1) males; 2) clofibrate-treated males; 3) females; and 4) pregnant females. A slow-diffusion/bound model was found to better describe the hepatic disposition of unchanged [3 H]palmitate than other pharmacokinetic models. The L-FABP levels followed the order: pregnant female Ͼ clofibrate-treated male Ͼ female Ͼ male. Levels of other intrahepatic proteins did not differ significantly. The hepatic extraction ratio and mean transit time for unchanged palmitate, as well as the production of low-molecular-weight metabolites of palmitate and their retention in the liver, increased with increasing L-FABP levels. Palmitate metabolic clearance, permeability-surface area product, retention of palmitate by the liver, and cytoplasmic diffusion constant for unchanged [3 H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [ 3 H]palmitate and its lowmolecular-weight metabolites in perfused rat livers is related to levels of L-FABP and not those of other intrahepatic proteins.clofibrate; pregnancy; multiple indicator dilution; hepatic extraction ratio; cytoplasmic diffusion constant NONESTERIFIED, LONG-CHAIN fatty acids (hereafter referred to as fatty acids) play a vital role in many cellular processes. They are an important source for cellular energy and form the building blocks from which various cellular components are synthesized. Some fatty acids are precursors for biological mediators, whereas others may interact with the cell membrane to regulate various cellular functions. Uptake of fatty acids has been shown to parallel the level of liver fatty acid binding protein (L-FABP) (22).L-FABP levels are known to be gender dependent, with females showing higher levels than males (25). L-FABP is also altered in various conditions, such as pregnancy and clofibrate treatment (6,26,31). Although the variation in the content of various intrahepatic proteins in liver disease has been used to account for the uptake, binding, and metabolism of solutes (20), the influence of intrahepatic proteins other than L-FABP [e.g., microsomal protein (MP), cytochrome P-450 (CYP), albumin (Alb), and glutathione S-transferase (GST)] on the hepatic disposition of [ 3 H]palmitate has been studied to a limited extent. Most studies investigating the fatty acid uptake into the liver have used isolated hepatocytes with some studies using intact livers (26,38).In this work, we examined the relationship between the hepatic pharma...

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“…It is generally recognized that the transmembrane uptake of fatty acids in the liver is driven by plasma membrane fatty acid transporters [membrane proteins for fatty acid translocase (FAT)/CD36; membrane FABP; and fatty acid transport protein (FATP)] and the cytosolic transport of fatty acids associated with cytosolic FABP or caveolin-1 (1,3,9,12,18,39). These hepatic transport processes appear to be key rate determinants of palmitate hepatic extraction.…”

Section: Ajp-gastrointest Liver Physiolmentioning

confidence: 99%

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

Hung

Siebert²,

Chang³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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3 H]palmitate and its low-molecular-weight metabolites in perfused normal and steatotic rat liver were studied using the multiple indicator dilution technique and a physiologically based slow diffusion/bound pharmacokinetic model. The steatotic rat model was established by administration of 17␣-ethynylestradiol to female Wistar rats. Serum biochemistry markers and histology of treated and normal animals were assessed and indicated the presence of steatosis in the treatment group. The steatotic group showed a significantly higher alanine aminotransferaseto-aspartate aminotransferase ratio, lower levels of liver fatty acid binding protein and cytochrome P-450, as well as microvesicular steatosis with an enlargement of sinusoidal space. Hepatic extraction for unchanged [ 3 H]palmitate and production of low-molecular-weight metabolites were found to be significantly decreased in steatotic animals. Pharmacokinetic analysis suggested that the reduced extraction and sequestration for palmitate and its metabolites was mainly attributed to a reduction in liver fatty acid binding protein in steatosis.17␣-ethynylestradiol; hepatic palmitate disposition NONALCOHOLIC FATTY LIVER DISEASE is increasingly recognized as a major health burden and probably the most common of all liver disorders (10,22). The prevalence of excessive hepatic fat accumulation in the general population in the United States and other Western countries has been estimated to be 20 -30% (19,22,23). In the majority of cases, the condition does not develop into more severe liver disease, although ϳ20 -30% of patients at the time of diagnosis show signs of steatohepatitis and are consequently at a higher risk to progress to cirrhosis, liver failure, or hepatocellular hepatoma (1a, 6, 25). The effects of excess of intracellular fatty acid concentrations, oxidant stress, ATP depletion, and mitochondrial dysfunction apparently all contribute in different ways to the subsequent hepatocellular injury, but mitochondrial dysfunction is thought to play an especially important role in the development of the condition (23).A question remains, however, as to what are the physiological and metabolic changes occurring in the very early (and undiagnosed) stages of fatty liver disease. To date, the hepatic kinetics-associated free fatty acid disposition and metabolism in the presence of lipid deposits in hepatic tissue has been poorly characterized. We have recently related the hepatic disposition kinetics of palmitate and its low-molecular-weight metabolites with a number of quantitative parameters defining different pathological liver conditions using an in situ rat liver perfusion study (12). In the present study, we sought to examine whether the kinetics of palmitate were affected by fatty liver disease in the rat. In doing so, we also collected a range of biochemical and histological parameters to examine possible correlations. Steatosis in rats was induced by administration of 17␣-ethinylestradiol (30). Also, we sought to mimic the hepatic fatty acid accumulation and ...

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The capillary transport system for free fatty acids in the heart.

Cited by 45 publications

References 44 publications

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

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