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

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 A 2 (TXA 2 ) receptor antagonist, daltroban, even though HCs do not express TXA 2 receptors.

Induction of Functional Anaphylatoxin C5a Receptors on Hepatocytes by In Vivo Treatment of Rats with IL-6

“…4). As shown previously (27), in perfused livers of control animals, these rrC5a-induced metabolic and hemodynamic effects were completely inhibited by the prostanoid synthesis inhibitor indomethacin and the thromboxane A 2 receptor antagonist daltroban, indicating that rrC5a acted indirectly on HC via prostanoid release from nonparenchymal cells expressing C5aR (27). These results were independent of whether untreated animals (Fig.…”

“…In contrast to these findings, C5aR mRNA (22) and protein (23) were expressed by Kupffer cells, hepatic stellate cells, and (weakly) sinusoidal endothelial cells but not by HC isolated from normal rat liver. This expression pattern was in line with functional studies demonstrating that recombinant rat C5a (rrC5a) activated glycogen phosphorylase (GPH) (24,25) and induced glucose output (26,27) in HC indirectly by stimulating PG and thromboxane release from Kupffer cells (24) and hepatic stellate cells (25). Analogously, C5a induced the synthesis of acute phase proteins in HC also indirectly by initiating proinflammatory cytokine formation by Kupffer cells (28).…”

“…In normal livers in which the HC are devoid of C5aR, the anaphylatoxin cannot enhance glucose output from HC directly but only indirectly by stimulating the release of prostanoids from Kupffer cells and hepatic stellate cells (24 -28). Thus, the C5a-dependent increase in glucose output from perfused livers of normal rats can be inhibited by the cyclooxygenase inhibitor indomethacin and the thromboxane receptor antagonist daltroban (27). Similarly, the C5a-dependent activation of GPH cannot be demonstrated in HC monocultures but only in cocultures of HC with prostanoid-secreting Kupffer cells (24) or hepatic stellate cells (25).…”

“…reactions in HC such as glucose release (26,27) or acute phase protein synthesis (28); it can only act indirectly via the release of prostanoids or cytokines, respectively, from Kupffer cells (26,28) and hepatic stellate cells (27), which bear the C5aR (22,23). During prolonged systemic or local hepatic inflammation the pattern of receptor expression on liver cells may change.…”

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

“…12). Prostaglandins released by KC increase glycogen degradation in hepatocytes significantly 50,51 and changes in prostaglandin release by KC will therefore affect glycogen stores in hepatocytes. Dexamethasone is a potent inhibitor of the prostaglandin synthesis and will consequently affect glycogen metabolism.…”