by two major endothelin receptors, endothelin A (ET A ) and Hepatic stellate cells are similar to tissue pericytes endothelin B (ET B ). 2-3 ET A receptors are abundant on vascuand have been shown to be contractile. In this study, we lar smooth muscle cells, have a high affinity for endothelinexamined the effects of known mediators of stellate cell 1, produce sustained contraction of vascular smooth muscle contraction on portal pressure in rat livers after carbon cells, and mediate vasoconstriction. 3 In contrast, ET B receptetrachloride induced injury (including cirrhosis) and tors bind both endothelin-1 and endothelin-3 with equal affininvestigated the contractility of stellate cells as a funcity. The ET B receptor appears to mediate either vasoconstriction of liver injury. Sarafotoxin S6C, an endothelin B tion or vasorelaxation depending on tissue type. 4 As such, (ET B ) receptor agonist, had minor effects on portal presthe endothelins are implicated in normal physiological as sure when perfused into normal livers at concentrations well as pathological responses. known to elicit stellate cell contraction (2 nmol/L). In Early work in liver has shown that endothelin-1 and endocontrast, both endothelin-1 (2 nmol/L) and angiotensin thelin-3 perfused into the portal system results in elevation II (8.6 nmol/L) caused a rapid and pronounced rise in of portal pressure and an increase in glycogenolysis. [5][6][7] Addiportal pressure. The effects of sarafotoxin S6C (a potent tionally, endothelin-1 may mediate sinusoidal vasoconstricstellate cell contractile agonist) on portal pressure were tion induced by ethanol.8 While the precise mechanism by greater in cirrhotic than normal liver, whereas those of which endothelin-1 and endothelin-3 cause vasoconstriction angiotensin II were unchanged after liver injury. Endoin liver is unknown, it has been proposed that they act on thelin-1 and sarafotoxin S6C The tent with its inhibitory effect on stellate cell contraction.most compelling evidence that endothelin may mediate sinuWe conclude that stellate cell contractility increases soidal vasoconstriction via its effects on stellate cells stems with progressive liver injury and is proportional to the from work directly showing their contraction in response to degree of stellate cell activation, becoming most promiendothelin-1 and endothelin-3. [13][14][15] nent in the cirrhotic liver. Endothelin-stimulated conDuring liver injury, stellate cells undergo a process charactraction of stellate cells in cirrhotic liver may contribute terized by loss of retinoid droplets, enhanced collagen producto increased intrahepatic resistance and portal prestion, and expression of smooth muscle a actin, which has sure. (HEPATOLOGY 1996;24:233-240.) been termed ''activation''. 16 It occurs spontaneously in cultured stellate cells, and in vivo during liver injury.17 Further The three known endothelins comprise a family of homolo-studies have indirectly suggested that myofibroblasts (i.e., gous 21 amino acid peptides.1,2 While they have diverse ef-...
Kinetic analysis of the uptake of carbon-14-labeled oleate in a single-pass perfusion of rat liver and saturable and specific binding of iodine-125-labeled albumin to hepatocytes in suspension suggest the existence of a receptor for albumin on the liver cell surface. The putative receptor appears to mediate uptake of albumin-bound fatty acids by the cell and may account for the efficient hepatic extraction of many other substances tightly bound to albumin.
In hemochromatosis and other disorders associated with iron overload, a significant fraction of the total iron in plasma circulates in the form of low molecular weight complexes not bound to transferrin. Efficient and unregulated clearance of this form of iron by the liver may account for the hepatic iron loading and toxicity that characterize these diseases. We tested this possibility by examining the hepatic removal process for representative iron complexes in the single-pass perfused rat liver. Hepatic uptake of both ferrous and ferric 55Fe from ultrafiltered human serum was found to be highly efficient and effectively irreversible (single-pass extraction of 1 MM iron, 58-75%). Similar high efficiencies were seen for iron complexed to specific physiologic and nonphysiologic coordinators, including histidine, citrate, fructose, oxalate and glutamate, and tricine. Because of lower plasma flow rates, single-pass extraction of these iron complexes in vivo should be even greater. Autoradiography confirmed that most iron had been removed by parenchymal cells. Hepatic removal from Krebs-tricine buffer was saturable with similar kinetic parameters for ferrous and ferric iron (apparent K., 14-22 ,uM; V.,, 24-38 umol min-' g liver-'). These findings suggest that high levels of non-transferrin-bound iron in plasma may be an important cause of hepatic iron loading in iron overload states.
Albumin binding is a crucial determinant of bilirubin clearance in health and bilirubin toxicity in certain disease states. However, prior attempts to measure the affinity of albumin for bilirubin have yielded highly variable results, reflecting both differing conditions and the confounding influence of impurities. We therefore have devised a method based on serial ultrafiltration that successively removes impurities in [ 14 C]bilirubin until a stable binding affinity is achieved, and then we used it to assess the effect of albumin concentration and buffer composition on binding. The apparent binding affinity of human serum albumin for [ 14 C]bilirubin was strongly dependent on assay conditions, falling from (5.09 ؎ 0.24) ؋ 10 7 liters/mol at lower albumin concentrations (15 M) to (0.54 ؎ 0.05) ؋ 10 7 liters/mol at higher albumin concentrations (300 M). To determine whether radioactive impurities were responsible for this change, we estimated impurities in the stock bilirubin using a novel modeling approach and found them to be 0.11-0.13%. Formation of new impurities during the study and their affinity for albumin were also estimated. After correction for impurities, the binding affinity remained heavily dependent on the albumin concentration (range (5.37 ؎ 0.26) ؋ 10 7 liters/mol to (0.65 ؎ 0.03) ؋ 10 7 liters/ mol). Affinities decreased by about half in the presence of chloride (50 mM). Thus, the affinity of human albumin for bilirubin is not constant, but varies with both albumin concentration and buffer composition. Binding may be considerably less avid at physiological albumin concentrations than previously believed.
Female liver clears long-chain fatty acids from plasma more rapidly than male liver, and yet the basis for this sex difference is poorly understood. We tested the hypothesis that cytosolic fatty acid binding protein (FABP), which is more concentrated in female liver, may enhance fatty acid utilization by increasing the rate of transport through the cytoplasm. We modified the technique of fluorescence recovery after laser photobleaching to measure the cytoplasmic diffusion rate of the fluorescent long-chain fatty acid 12-N-methyl-(7-nitrobenz-2-oxa-1,3-diazol)aminostearate (NBD-stearate) in cultured hepatocytes from female and male rats. NBD-stearate was used because its hepatic handling is similar to natural fatty acids. After uptake, NBD-stearate distributed uniformly in the cytoplasm but was excluded from the nucleus. Intracellular transport occurred by diffusion with no detectable convective flux. The cytoplasmic diffusion rate at 37 degrees C was 65% greater in female cells than in male cells (mean +/- SE, 5.03 +/- 0.37 vs. 3.05 +/- 0.21 x 10(-9) cm2/s respectively; P < 0.001) and was two to three orders of magnitude slower than for either unbound NBD-stearate or FABP in water. A correspondingly greater fraction of cellular NBD-stearate was found in the aqueous cytosol in females (35.1 +/- 7.0 vs. 18.2 +/- 2.7%), suggesting that FABP reduces binding of NBD-stearate to immobile cytoplasmic membranes. These data indicate that intracellular transport of NBD-stearate, a typical amphipathic molecule, is slowed by binding to cytoplasmic membranes. The primary function of soluble binding proteins such as FABP may be to enhance the diffusive fluxes of their ligands by reducing membrane binding. If cytoplasmic transport of rapidly metabolized fatty acids such as palmitate is similarly slow, substantial concentration gradients could develop within the cytoplasm of hepatocytes at steady state. By catalyzing these diffusive fluxes, FABP may regulate fatty acid metabolism.
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