Increase by Anaphylatoxin C5a of glucose output in perfused rat liver via prostanoids derived from nonparenchymal cells: Direct action of prostaglandins and indirect action of thromboxane A2 on hepatocytes

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Abstract
In the perfused rat liver the anaphylatoxin C5a enhanced glucose output, reduced flow, and elevated prostanoid overflow. Because hepatocytes (HCs) do not express C5a receptors, the metabolic C5a actions must be indirect, mediated by e.g. prostanoids from Kupffer cells (KCs) and hepatic stellate cells (HSCs), which possess C5a receptors. Surprisingly, the metabolic C5a effects were not only impaired by the prostanoid synthesis inhibitor, indomethacin, but also by the thromboxane A2 (TXA2) receptor antagonist, daltroban, even though HCs do not express TXA2 receptors. TXA2 did not induce prostaglandin (PG) or an unknown factor release from KCs or sinusoidal endothelial cells (SECs), which express TXA2 receptors, because (1) daltroban did neither influence the C5a-induced release of prostanoids from cultured KCs nor the C5a-dependent activation of glycogen phosphorylase in KC/HC cocultures and because (2) the TXA2 analog, U46619, failed to stimulate prostanoid release from cultured KCs or SECs or to activate glycogen phosphorylase in KC/HC or SEC/HC cocultures. In the perfused liver, Ca2+-deprivation inhibited not only flow reduction but also glucose output elicited by C5a to similar extents as daltroban. Similarly, in the absence of extracellular Ca2+, flow reduction and glucose output induced by U46619 were almost completely prevented, whereas glucose output induced by the directly acting PGF2α was only slightly lowered. Thus, in the perfused rat liver PGs released after C5a-stimulation from KCs and HSCs directly activated glycogen phosphorylase in HCs, and TXA2 enhanced glucose output indirectly mainly by causing hypoxia as a result of flow reduction.