Uptake of labeled palmitate by the intact liver: role of intracellular binding sites.

Goresky, Carl A.; Daly, Declan; Mishkin, Seymour; Im, Arias

doi:10.1152/ajpendo.1978.234.6.e542

Cited by 32 publications

(28 citation statements)

References 26 publications

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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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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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“…Goresky and coworkers (38) have determined the rate constants for palmitate transport in the intact dog. Their results suggest that metabolism should be relatively more important than influx in determining the rate of hepatic palmitate removal at steadystate in vivo.…”

Section: Discussionmentioning

confidence: 99%

Uptake of oleate from albumin solutions by rat liver. Failure to detect catalysis of the dissociation of oleate from albumin by an albumin receptor.

Weisiger¹,

L²

1987

J. Clin. Invest.

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The hepatic removal of albumin-bound substances from plasma requires that they dissociate from albumin. Using indirect methods, we and others have proposed that dissociation may be catalyzed by interaction of albumin with the liver cell surface. This study looked for direct evidence of catalysis by comparing the rate of dissociation of oleate from albumin in vitro with the rate observed within the sinusoids of perfused rat liver. No evidence for catalysis was found. The rate of hepatic oleate removal from dilute albumin solutions did not exceed but instead closely paralleled the rate predicted from the in vitro dissociation rate constant (0.14 s-'). These results suggest that under some conditions the liver can remove unbound material from the sinusoids faster than it can be replenished by dissociation from albumin, resulting in dissociation-limited removal. However, dissociation of oleate does not appear to be catalyzed by the liver.

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“…If, how-efflux rates following a brief period of uptake. 37,38 ever, P m ӷ P c , then a large concentration gradient will form Membrane carriers for bile acids have been defined in both at steady-state in the presence of an effective biliary secretion the plasma and canalicular poles of the liver cell. 39 They are mechanism † (Fig.…”

Section: Permeability Of the Cytoplasmmentioning

confidence: 99%

“…78 Although convection and vesicular tate, which competes with fatty acids for binding to fatty acid transport may contribute significantly to cytoplasmic trans-binding protein, greatly reduced uptake rates by displacing port of some amphipathic molecules, 79-82 most cytoplasmic fatty acids from the FABP onto intracellular membranes 100 transport is believed to occur by diffusion of the amphipath and promoting efflux from the cell. 37 Indeed, the steady upwhile it is bound to cytoplasmic binding proteins. 78,83,84 take rate of fatty acids by liver cells correlates closely with A role for soluble binding proteins in transport has long the soluble (protein-bound) fraction in the cytoplasm (Fig.…”

Section: Binding Proteinsmentioning

confidence: 99%

When is a carrier not a membrane carrier? The cytoplasmic transport of amphipathic molecules

Weisiger¹

1996

Hepatology

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lular water layers. This article reviews how this process After entering the cell, small molecules must penetrate works and how it may fail in certain disease states. the cytoplasm before they are metabolized, excreted, or can convey information to the cell nucleus. Without effi-THE VARIETY OF SOLUBLE BINDING PROTEINS cient cytoplasmic transport, most such molecules would efflux back out of the cell before they could reach their Many biologically important compounds are only sparingly targets. Cytoplasmic movement of amphipathic mole-soluble in water. For example, the solubility of long-chain cules (e.g., long-chain fatty acids, bilirubin, bile acids) is fatty acids at physiological pH is õ10 mmol/L, 7,8 while that greatly slowed by their tendency to bind intracellular of bilirubin is õ1 nmol/L. 9,10 Other metabolites with low solustructures. Soluble cytoplasmic binding proteins reduce bilities include phospholipids, 11 hydrophobic bile acids, 12 retithis binding by increasing the aqueous solubility of their noids, 13 coenzyme A-esters, 14 cholesterol, 15 thyroid and steligands. These soluble carriers catalyze the transport of roid hormones, 16 and a wide variety of exogenous drugs and hydrophobic molecules across hydrophilic water layers, toxins collectively termed ''organic anions.'' Solubility of these just as membrane carriers catalyze the transport of hy-molecules may be greatly increased by binding proteins. drophilic molecules across the hydrophobic membrane These proteins provide mobile hydrophobic binding sites that core. They even display the kinetic features of carrier-allow amphipathic molecules to penetrate into and across mediated transport, including saturation, mutual com-aqueous layers that would otherwise block transport. 17 This petition between similar molecules, and countertrans-function has been compared with boats (the binding proteins) port. Recent data suggest that amphipathic molecules carrying nonswimming passengers (the amphipaths) across cross the cytoplasm very slowly, with apparent diffusion a river (the water layer). 18 Cytoplasm contains a large numconstants 10 2 to 10 4 times smaller than in water. By mod-ber of soluble binding proteins. These include fatty acid bindulating the rate of cytoplasmic transport, cytosolic bind-ing proteins, 19 of glutathione S-transferases with overlapping specificities. 26 Albumin serves a similar function outside the cell by carrying long chain fatty acids and numerous organic anions across The oldest paradigm in transport physiology is that cell unstirred plasma layers near the cell surface. 17 membranes provide the major barrier to cellular uptake and secretion. This is clearly true for hydrophilic molecules such

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Uptake of labeled palmitate by the intact liver: role of intracellular binding sites.

Cited by 32 publications

References 26 publications

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

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

Uptake of oleate from albumin solutions by rat liver. Failure to detect catalysis of the dissociation of oleate from albumin by an albumin receptor.

When is a carrier not a membrane carrier? The cytoplasmic transport of amphipathic molecules

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