Hepatocyte heterogeneity in response to extracellular ATP

Abstract

1. The metabolic and hemodynamic effects of extracellular ATP in perfused rat liver were compared during physiologically antegrade (portal to hepatic vein) and retrograde (hepatic to portal vein) perfusion. ATP in concentrations up to 100 pM was completely hydrolyzed during a single liver passage regardless of the perfusion direction.2. The ATP(20 pM)-induced increases of glucose output, perfusion pressure and ammonium ion release seen during antegrade perfusions were diminished by 85 -95% when the perfusion was in the retrograde direction, whereas the amount of Ca2+ mobilized from the liver was decreased by only 60%. The maximal rate of initial K + uptake following ATP was dependent on the amount of Ca2+ mobilized regardless of the direction of perfusion. In the presence of UMP (1 mM), an inhibitor of ATP hydrolysis by membrane-bound nucleotide pyrophosphatase, the effect of the direction of perfusion on the glycogenolytic response to ATP (20 pM) was largely diminished.3. For a maximal response of glucose output, Ca2+ release and perfusion pressure to extracellular ATP, concentrations of about 20 pM, 50 pM and 100 pM were required during antegrade perfusion, respectively. These maximal responses could also be obtained during retrograde perfusion, but higher ATP concentrations were required (120 pM, 80 pM, above 200 pM, respectively).4. 14C02 production from [I -14C]glutamate which occurs predominantly in the perivenous hepatocytes capable of glutamine synthesis was stimulated by extracellular ATP (20 pM); it was only slightly affected by the direction of perfusion. In antegrade perfusions, ATP (20 pM) increased I4CO2 production from 88 to 162 nmol g-lmin-', compared to an increase from 91 to 148 nmol g-' min-' in retrograde perfusion.5. The data are interpreted to suggest that (a) extracellular ATP is predominantly hydrolyzed by a small hepatocyte population located at the perivenous outflow of the acinus; (b) glycogenolysis to glucose is predominantly localized in the periportal area; (c) contractile elements (sphincters) exist near the inflow of the sinusoidal bed; (d) a considerable portion of the Ca2+ mobilized by ATP is derived from liver cells that do not contribute to hepatic glucose output.In liver, extracellular ATP (for review see [l]) stimulates glycogenolysis [2-61 and citric acid cycle flux [7], increases the portal pressure [S, 61, induces K+ [6,[9][10][11] and Ca2+ fluxes [5, 6, 81 diacylglycerol following an activation of the P,-purinergic receptor [18 -211. Besides ATP and ADP, other extracellular nucleoside phosphates, such as UTP and UDP are also potential regulators of hepatic metabolism or microcirculation. Interestingly, ATP leads to responses qualitatively and quantitatively different from those observed with UTP and there is some indication that both nucleotides may act on different receptors [6]. Extracellular ATP and other purine and pyrimidine nucleotides are hydrolyzed by isolated hepatocytes and livers in vitro and in vivo [Il, 22, 231. Among the enzymes involved in ATP hydrolysis...

Hepatocyte heterogeneity in response to icosanoids

“…The data indicate a preferential inactivation of icosanoids in the perivenous region of the acinus, near the outflow of the sinusoidal bed, whereas their site of action is more upstream. The data are in line with a hypothesis that a major function of a perivenous cell population near the outflow of the sinusoidal bed ('perivenous scavenger cells') is to inactivate or eliminate a variety of potentially toxic compounds which escaped periportal disposal, including ammonia, which escaped periportal urea synthesis [34]), extracellular nucleotides [35] and icosanoids.…”

“…The temperature was 37 "C. Perfusions were carried out either in the antegrade (portal to caval vein) or the retrograde (caval to portal vein) direction. Changes of the perfusion direction in the individual perfusion experiment occurred within 3 -5 s and were performed as described previously [34,35]. The perfusion flow was 3.2-4.5 ml min-' (g liver)-' and was constant within 5% throughout the individual experiment and also after repeated changes of the perfusion direction.…”

Increase of glucose and lactate output and decrease of flow by human anaphylatoxin C3a but not C5a in perfused rat liver

“…The inactivation of C3a by the liver might play an important role in its self-protection during systemic generation of the anaphylatoxin. The cells at the entrance of the sinusoids might act as protecting scavengers as proposed previously [24]. Thus, it seems unlikely that C3a generated systemically in the circulation has an effect on liver metabolism or hemodynamics.…”

Periportal and perivenous hepatocytes respond equally to glycogenolytic agonists

“…KA values (agonist concentrations at which half maximal activation is obtained) have been computed as described previously [3,[13][14][15] These data do not however exclude an in vivo occurrence of zonation of hormonal glycogenolysis. Indeed, using a perfused system, H~iussinger et al [16] reported on liver heterogeneity in response to extracellular ATP, the periportal area being more responsive to ATP than the perivenous hepatocytes. These data are not necessarily in contradiction with our findings showing no different glycogenolytic capacity between hepatocytes originating from the two zones.…”