Platelet-activating factor and its metabolic effects

Prostaglandins 0 Longman

Leukotrienes and Essential Group UK Ltd IWI

Fatty

Acids

(1991)

44.1-10

Review

Platelet-activating Factor and its Metabolic Effects R. D. Evans, P. Lund* and D. H. Williamson* N@ieM Department of Anaesthetics and *Metabolic Research Laboratory, Cli,rical Medicine, to DHW)

Radcliffe Infirmary,

Nuffield Department of Woodstock Road, Oxford OX2 6HE, fiK (Rep& requests

INTRODUCTION

especially within the liver, and the likely involvement of further lipid mediators, the eicosanoids

Platelet-activating factor (PAF) is a potent, biologically active phospholipid, first described in 1971 as a mediator of IgE-induced anaphylaxis in the rabbit (1.2). It was characterised in 1979 by several groups as I-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (for historical account, see 3, 4). This established its identity with the antihypertensive polar renomedullary lipid simultaneously under investigation and emphasised the diversity of actions of this phospholipid. Structure-function relationships of the molecule, including those of the alkyl moiety, are discussed elsewhere (5-7). Alternative terms include acetylglyceryl ether phosphocholine (AGEPC), (alkylacetylalkylacetylglycero-phosphocholine GPC) and PAF-acether (acet for acetate and ether for the alkyl bond). Whilst ‘PAF’ is now commonly accepted, it should be emphasised that this is misleading in view of its diverse actions. Its true physiological function, possibly immunoregulation and haemostasis, is still uncertain, though presumably is important since PAF is found in all mammals studied. PAF is highly toxic in excess or when administered exogenously (3). and has been implicated in the pathogenesis of a variety of clinical inflammatory states, including septic shock, anaphylaxis and adult respiratory distress syndrome/shock lung (8). Since these pathological states are themselves associated with characteristic metabolic changes, the investigation of metabolic effects of inflammatory mediators seems a logical research strategy. Our intention is to concentrate on this aspect of PAF research, which has paralleled structural and functional investigations into PAF, and coincided with similar studies into the cffccts of the peptide cytokines (for review, see 9) and other putative inflammatory mediators and actiological agents of shock states (10). A ‘spinoff’ from these studies has been the insight gained into paracrinc mechanisms of cell-cell communication,

(11). PAF is synthesised by a wide variety of mammalian cells, including leukocytes, macrophages, platelets, renal medullary cells and endothelial cells (3, 12). The chemistry of its synthesis has been elucidated (5) and comprises a de novo pathway, thought to provide basal physiological levels of PAF, and a ‘remodelling’ pathway, capable of considerable PAF synthesis and secretion under stimulus conditions (3, 5). Physiological stimuli of PAF secretion are uncertain, but the calcium ionophore A23187, most inflammatory agents, including zymosan and oleic acid, and the cytokines tumour necrosis factor-o (TNF-(Y) and interleukin-1 (IL-l) (13), stimulate PAF production and secretion. PAF receptors have been found on rabbit and human platelets (though not on rat platelets) (14), leukocytes (15), macrophages (16)) including hepatic Kupffer cells (17), human lung tissue (18) and liver plasma membranes (19). The rabbit lung receptor has recently been cloned and found to belong to the superfamily of receptors coupled to GTP-binding proteins (G proteins) (20). PAF is inactivated by an acetylhydrolase found in an intracellular (cytosolic) site (21) and as a plasma enzyme associated with HDL and LDL (22). The mechanism of intracellular signal transduction following PAF-receptor binding is still uncertain, but the observation that phosphoinositide hydrolysis occurs (23) provided the first clue to metabolic effects of PAF in liver.

PAF AND CARBOHYDRATE

METABOLISM

Effects in vivo

PAF infusion in starved adult rats in vivo has effects on carbohydrate metabolism similar to endo-

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toxaemia, i.e. increased plasma glucose and lactate, and an increased rate of glucose appearance (24). These changes were associated with increased plasma glucagon and catecholamines and all could be prevented by complete adrenergic blockade (24). This suggests that, in vivo at least, some actions of PAF are indirect and are mediated by catecholamines, but PAF may still be a functional intermediate in the complex pathway whereby sepsis (endotoxin), and other ‘stress’ states such as burns, lead to metabolic alterations. Endotoxin and burns (25,26) stimulate PAF production in vivo and the PAF antagonist SRI-63-675 prevents: 1) burninduced changes in glucose metabolism (27) (though probably as a secondary phenomenon to haemodynamic effects) and 2) endotoxin-induced changes in ‘stress’ hormones (catecholamines and glucagon) and glucose and lactate levels in rats (28). Hepatic effects, in vitro In 1983, Shukla et al (23) reported a potent effect of PAF (5 x 10-‘“M) on polyphosphoinositide metabolism in isolated rat hepatocytes. They found a rapid decrease in [32Pi]phosphatidylinositol 4,5bisphosphate, and the [32P] content of phosphatidylinositol 4-phosphate in these cells; results similar to those seen in washed rabbit platelets (29) which would imply a role for calcium and/or protein kinase C in PAF signal transduction. Several hormones, including ar-adrenergic agonists, vasopressin and angiotensin II, which influence membrane phosphoinositide metabolism (30-34), also stimulate hepatic glycogenolysis. This led Olson and colleagues to examine the effect of PAF on liver glycogenolysis. In perfused (non-recirculating) liver from fed rats, PAF (2 x 10-loM) caused a transient 300% increase in glucose output in perfusate effluent, an effect not reproduced by 1-0-alkyl-sn-glycerol3-phosphocholine (lyso-PAF) or stereoisomer, the 3-O-alkyl-2-acetyl-sn-glycerol 1-phosphocholine (23). Homologous desensitisation of the glycogenolytic response to PAF occurred following repeated PAF infusion, but the hepatic response to subsequent phenylephrine or glucagon infusion was unaffected (35). The PAF effect was sensitive to perfusate calcium concentration, but no calcium efflux was observed (35) (contrast the effects of cu-adrenergic agonists, vasopressin and angiotensin II). Desensitisation is a general feature of PAF action in a variety of cell systems (35), and may be a function of receptor down-regulation and/or depletion of intracellular calcium pools distinct from those mobilised by the endocrine hormones. PAF induced extracellular calcium uptake has been observed in rabbit platelets and polymorphonuclear leukocytes (36, 37). Subsequently, however, the studies of glycogen

metabolism demonstrated that PAF did not stimulate glycogenolysis (38-40) nor activate glycogen phosphorylase (38, 39) in isolated hepatocytes from fed rats, whilst glucagon and adrenaline caused phosphorylase activation and glucose release from the same cells (38). Endocrine hormones can stimulate rat liver glycogenolysis by CAMP-dependent or CAMP-independent mechanisms. The former (e.g. glucagon) involving activation of adenylate cyclase and CAMP-dependent protein kinase with no effect on phosphoinositide metabolism (41); the latter (e.g. a-adrenergic agonists, vasopressin and angiotensin II) by promotion of intracellular calcium mobilisation with direct glycogen phosphorylase activation, via phosphoinositide metabolism (42). The inference from this work was that PAF stimulated hepatic glycogenolysis by a mechanism that was distinct from either of the two main groups of hepatic agonist endocrine hormones (CAMP-dependent and Ca2+-dependent) and further, that this mechanism was probably indirect, not primarily involving hepatocytes despite the observed changes in phosphoinositide metabolism in these cells following exposure to PAF (23, 38). A possible mechanism emerged when the same laboratory found a concomitant increase in portal venous pressure in their isolated rat livers when perfused with PAF, indicating hepatic vasoconstriction (43). The glucose release and increased portal pressure were closely correlated in time, tachyphylaxis, and dose- and calcium-dependency; the calcium channel antagonist verapamil inhibited both effects of PAF (43). CAMP levels were unchanged by PAF but ADP levels were significantly increased, with the conclusion that glycogenolysis resulted from regional liver hypoxia secondary to reduced hepatic perfusate flow (43). Support for this view came from earlier work by the same group in the same model, in which PAF (2 x lo-“M) was found to cause a decrease in hepatic oxygen consumption accompanied by a decreased rate of acetoacetate output and increased lactate output, in contrast to the effects of phenylephrine (35). Vasoactive properties have been ascribed to PAF in a number of sites, including dilation in perfused rat hindquarter vessels (44) and constriction in guinea-pig pouch microvasculature (45) (for review see 12); increased portal vein pressure was demonstrated in dog in vivo (46) and decreased blood flow to liver and other tissues in the rat (47). of the PAF-induced phosThe teleology phatidylinositol 4,5-bisphosphate breakdown in hepatocytes (23) remains uncertain, because of the failure so far to identify a metabolic target system. Charest et al (33) found rat hepatocyte myo-inositol trisphosphate ( IP3) was increased by vasopressin , adrenaline, angiotensin and ATP (with concomitant increase in intracellular calcium and phosphorylase

Platelet-activating

activity) but not by glucagon or PAF, suggesting a role for IP3 as a second messenger. Thus, the absence of effects of PAF on glycogenolysis in hepatocytes, despite stimulation of phosphinositide metabolism, may be due to the failure to increase IP3. Similarly, 12-O-tetradecanoylphorbol-13-acetate (phorbol ester), a potent activator of protein kinase C, stimulates hepatic glycogenolysis in perfused rat liver but not in isolated hepatocytes (48). Again this effect is sensitive to extracellular calcium concentration and calcium channel antagonists (48) but presumably independent of changes in IP3. The failure of phorbol esters, which mimic diacylglycerol, and PAF to stimulate glycogenolysis directly in hepatocytes throws doubt on a role for signal transduction via inositol phosphates in this process. Specific inhibition of the effect of PAF on glycogenolysis and portal venous pressure in the perfused liver by the PAF-receptor antagonists U66985 and CV3988 (49) suggested that the PAF effect was indeed mediated via specific receptors. The effect of the a-adrenergic agonist phenylephrine on hepatic glycogenolysis is not reversed by PAF antagonists (49), but P-adrenergic stimulation (isoprenaline) did inhibit the glycogenolytic and vasoconstrictive effect of PAF in the perfused liver (50), again suggesting an indirect mechanism whereby PAF causes hypoxia secondary to reduced portal (perfusate) flow, since p agonists cause hepatic vasodilation. Further evidence for a role of PAF in regulation of hepatic glycogenolysis was obtained when heataggregated IgG was found to increase glycogen phosphorylase content and stimulate glucose release from perfused liver of fed rats with an increase in the 1actate:pyruvate ratio in the perfusate effluent (surprisingly the latter was accompanied by increased 02 consumption) (51, 52). PAF activity was detected in the perfusate effluent in these experiments. Coinfusion of the cyclooxygenase inhibitor, indomethacin, prevented heat-aggregated IgGinduced glycogenolysis but not PAF-induced hepatic glycogenolysis (51), suggesting that heat-aggregated immune complexes stimulate intrahepatic PAF production by an eicosanoid-mediated mechanism. As found with PAF, the response of the perfused liver to the heat-aggregated IgG was Ca*+ sensitive (52). b*Adrenergic agonists inhibited the vasoconstriction and subsequent glycogenolysis (and PAF synthesis) induced in perfused rat liver by immune aggregates (53), suggesting a CAMPindependent mechanism for the response. Heat-aggregated IgG, like PAF (38), had no effect on glycogen phosphorylase or glucose release from isolated hepatocytes (53). Infusion of prostaglandin E2 (52), PGF2, (54), the thromboxane A2 analogues U46619 (55) and ONO-11113 (54) and leukotrienes C4 and D4 (56) mimicked the effects of

Factor and its Metabolic Effects

3

heat-aggregated IgG (and PAF) in the perfused liver, supporting earlier evidence, based on cyclooxygenase inhibition (40, 57), that the mechanism of PAF action involved intrahepatic eicosanoid metabolism. The finding of van Berkel and colleagues (58, 59) that prostaglandins, especially PGD2 (at high concentrations), were capable of stimulating glycogenolysis in isolated hepatocytes from fed rats, provides a possible link. This glycogenolytic effect was mimicked by conditioned medium from Kupffer and culture endothelial cells (59), though conditioned medium from non-parenchymal cells incubated with aspirin, an inhibitor of prostaglandin synthesis, had no effect (58). Eicosanoids are almost entirely produced by non-parenchymal cells (Kupffer and endothelial cells) in rat liver, and approximately half of that produced is PGD2 (60). PAF stimulates PGD2 production by isolated Kupffer cells (61). Since PAF receptors are found on Kupffer cells (17) and endothelial cells (13) and as tissue macrophages are sensitive to endotoxin or aggregated immune complexes (62), it is possible that PAF and phorbol ester (63) and endotoxin (62) binding to Kupffer cells elicits eicosanoid (PGD2) synthesis and release, which in turn acts as a paracrine effector, stimulating glycogenolysis in adjacent hepatocytes (62-65). This would explain the lack of direct effect of PAF (3%40), endotoxin (62) and phorbol ester (63, 66) on glycogenolysis in isolated hepatocytes, and the prevention of effects in perfused liver by inhibitors of cyclooxygenase (64) (for review, see 67). PGD2 binding to Kupffer cells is minimal (68). Further evidence for a paracrine mechanism for the effect of PAF on hepatic glycogenolysis followed with the demonstration that PAF produces dose-dependent increases in [3H]inositol phosphates in [3H]inositollabelled Kupffer cells and increased intracellular calcium concentrations (69). However, elegant though this explanation is, controversy remains. In a recent study (70), although PAF wag found to increase PGD2 and thromboxane B2 in perfused rat liver effluent, coinfusion of the cyclooxygenase inhibitor ibuprofen abolished the PGD2 production but not increased the vasoconstriction and hepatic glycogenolysis. Thromboxane B2 was similarly decreased by ibuprofen (70), apparently excluding cyclooxygenase products of arachidonic acid from the mechanism of PAF-stimulated hepatic glycogenolysis in vitro, and suggesting their production is coincidental. This is in contrast to the observed inhibition of PAF-induced glycogenolysis and vasoconstriction in perfused rat liver following pretreatment with another cyclooxygenase inhibitor, indomethacin (5, 12, 20, 21, 70). A possible explanation for the apparent contradictory results is the Ca*+ antagonist action of indomethacin (71,72), as well as its inhibition of protein kinases (73, 74).

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Since PAF action is associated with changes in Ca2+ metabolism (57, 75, 76), indomethacin may not be a reliable tool in this model to identify a cyclooxygenase-mediated mechanism. Support for this view is the fact that the glycogenolytic effect of phorbol esters in perfused liver is inhibited by indomethacin, but eicosanoid production is unchanged (77). In vivo, the PAF antagonist BN52021, but not the cyclooxygenase inhibitor sodium diclofenac, prevented the initial hyperglycaemic response to alloxan (thought to be due to hepatic glycogenolysis (78)) in rats but failed to prevent glucagon-induced stimulation of hepatic glycogen breakdown (79). However, the possibility exists that a lipooxygenase product (leukotriene) of arachidonic acid may be responsible for the paracrine mechanism discussed above. The recent discovery of a novel family of peptides (21 amino acids) - the endothelins (ET) - derived from cultured endothelial cells (80) has complicated the picture. When administered in vivo they have an initial vasodilator action (81) unrelated to PAF receptors or cyclooxygenase products (82), followed by more prolonged systemic vasoconstriction (83), the latter associated with inositol phosphate hydrolysis and increased intracellular calcium. Like PAF, ET-l causes dose-dependent vasoconstriction and increased portal pressure in the isolated perfused rat liver, with accompanying increased glycogenolysis and altered oxygen consumption (84). This was calcium-requiring but not influenced by OLor 8 agonists, angiotensin II, PAF or PAF antagonists (84); tachyphylaxis of the glycogenolytic but not the vasoconstrictive response to ET-l was seen (84). ET-l receptors have been demonstrated in rat liver membranes (85), and ET-l stimulates inositol phospholipid metabolism in isolated cultured hepatocytes and Kupffer cells (84). ET-l increases intracellular free calcium and, unlike PAF, potently stimulates glycogenolysis in isolated hepatocytes (85). ET-l is probably both a paracrine and endocrine hormone (86) and endotoxin stimulates endothelin release in rat (87). However, its relationship, if any, to PAF and eicosanoid action remains to be elucidated. PAF and foetal development Effects of PAF on glycogen metabolism are not confined to the liver. Another major site of glycogen deposition is the foetal lung (88). Glycogen depots in type II pneumocyte progenitor cells decrease in late gestation (89, 90) with concomitant appearance of surfactant-containing lamellar bodies (89, 90). At the same time PAF biosynthetic capacity and PAF concentration increase in the foetal (rabbit) lung (91, 92). Hoffman et al postulated that these events may be causal (91, 93, 94) - foetal lung PAF

synthesis causing pulmonary glycogenolysis with subsequent phospholipid (surfactant) synthesis. Support for this view is the demonstration of decreased foetal lung (and liver) glycogen following intrauterine injection (high doses) of PAF in rabbits (95), with increased lung, liver and plasma lactate concentration; effects that were prevented by pretreatment of the foetus with the PAF antagonist SRI-63-441 (95). Lung contains numerous cell types and paracrine and/or vasoactive effects may occur. Further evidence for a metabolic role for PAF in utero was provided by the demonstration that mouse (96, 97) and human (98) preimplantation embryos produce the phospholipid mediator in a manner positively correlated with pregnancy potential following embryo transfer (99); the PAF receptor antagonist SRI-63441 reduces implantation rate in mice (100). Exogenous PAF (again in high dose) increases the rate of lactate (97, 101) and glucose oxidative metabolism by preimplantation mouse embryos in vitro (lOl), suggesting a role for the PAF in the metabolic events of early pregnancy.

PAF AND LIPID METABOLISM Effects in vivo In addition to its essentially catabolic effects on carbohydrate metabolism in vivo (24) and in vitro (23), PAF also affects lipid metabolism in vivo. PAF administration to fed rats paradoxically caused increased synthesis of hepatic lipid (saponified and non-saponified classes) in a dose-dependent fashion and hypertriglyceridaemia (102). However, PAF did not stimulate lipogenesis in isolated hepatocytes (102), liver slices or isolated perfused livers from fed rats (RDE & DHW, unpublished experiments), or in adipose tissue in fed rats in vivo (102). The possibility arises that this increased lipogenesis could be secondary to increased intrahepatic glucose availability resulting from PAF-induced hepatic glycogenolysis (23). However, PAF stimulates hepatic lipogenesis at lower doses in vivo than those required to deplete hepatic glycogen content or cause hyperglycaemia (102). Increased hepatic lipid synthesis was accompanied by decreased plasma insulin (102), arguing against this hormone being involved. Furthermore, the effect of PAF on lipid metabolism could be prevented by the PAF receptor antagonist L659, 989, but not by indomethacin (102), suggesting that a cyclooxygenase-derived arachidonic acid metabolite is not a mediator. Increased hepatic lipogenesis and hypertriglyceridaemia in vivo is seen with another putative inflammatory/shock mediator, the cytokine TNF-e! (103); again, this effect has not been demonstrated in vitro. By contrast, the related

Platelet-activating

cytokine, IL-lp, does not stimulate hepatic lipid synthesis in glucose-fed rats in vivo (104). TNF-(U has a wide spectrum of effects on metabolism (9, 105); it stimulates glycogen breakdown in myotubes of the L6 muscle-cell line (106), but like PAF, stimulates hepatic lipogenesis at doses which have no effect on liver glycogen content and do not increase blood glucose, yet decrease plasma insulin (107). It is therefore possible that TNF-(x and PAF share a common messenger pathway; in addition, each can stimulate release of the other (13, 108). If this is the case, PAF, like TNF (9, lo), might be expected to inhibit adipose tissue lipoprotein lipase in vivo, leading to decreased plasma triacylglycerol disposal, and hypertriglyceridaemia. However, PAF has no effect on accumulation of an oral 14C-lipid load in white adipose tissue, although accumulation of 14C-lipid in brown adipose tissue is decreased to 40% of control values (107). PAF decreases i4C-lipid oxidation to 14COz (107), an effect also seen with TNF-o (109), and both substances decrease lipid absorption (107, 109). TNF-cx or endotoxin toxicity on the gastrointestinal tract is probably mediated by PAF (llO-112), but this toxicity and consequent decreased stomach emptying and/or absorption makes the hypertriglyceridaemia observed with both substances (102, 107, 109) even more striking. Whilst TNF-a may cause this increase in plasma triacylglycerol by a combination of increased hepatic VLDL secretion (increased fatty acid synthesis de novo and increased cycling of NEFA from adipose tissue) and decreased peripheral removal (decreased adipose tissue lipoprotein lipase) the relative role of ‘central’ and ‘peripheral’ mechanisms is by no means sure. The mechanism for the PAF-induced increase in hepatic lipogenesis remains uncertain. PAF increased circulating glycerol and NEFA when administered to fed rats in vivo (107), suggesting increased peripheral lipolysis (an effect also seen with TNF-ar (9, 105)). This might explain the hypertriglyceridaemia (102)) by increased hepatic re-esterification of NEFA and export as VLDL, but does not account for the stimulation of hepatic lipogenesis de novo (102). In addition, PAF caused decreased insulin secretion (102, 113), and increased catecholamines (24), together with the higher plasma NEFA, all of which might be expected to decrease liver lipid synthesis in vivo. However, the effect of catecholamines on liver metabolism in vivo is complex; a-adrenergic stimulation causes glycogenolysis (114) and vasoconstriction (50, 115), whilst /3-adrenergic stimulation causes hepatic vasodilation and increased hepatic blood flow (115, 116); indeed, B-adrenergic agonism can prevent the PAF-induced vasoconstriction and glycogenolysis of perfused rat liver (50). In order to investigate the role of endogenous catecholamines

Factor and its Metabolic Effects

5

in the mechanism of autacoid-induced increased PAF (and TNF-ar) were hepatic lipogenesis, administered to adrenalectomised rats in vivo (107). Adrenalectomy decreased hepatic lipogenesis in non-mediator-treated fed animals (107, 117), but PAF and TNF-ar still stimulated liver lipid synthesis and caused hypertriglyceridaemia, despite low plasma insulin (107). A possible distal mediator of PAF action on the liver is serotonin (5-hydroxytryptamine; 5HT), released from (rabbit) platelets following PAF stimulation (118); administration of 5HT to fed rats in vivo increases hepatic lipogenesis and elicits hypertriglyceridaemia, with no change in hepatic glycogen content (RDE & DHW, unpublished experiments).

PAF and diabetes Evidence for a ‘feedback’ mechanism between PAF and lipid metabolism has been demonstrated in that ketone bodies (acetoacetate and 3-hydroxybutyrate in pathologically relevant concentrations) increase A23187- and opsonised zymosan-stimulation of PAF production by human polymorphonuclear leucocytes in vitro (119); such a mechanism may amplify PAF-mediated biological responses, e.g. in diabetes. Ketone body-derived acetyl-CoA may be utilised for the acetyl moiety of PAF; Benveniste et al have demonstrated increased PAF ‘synthesis in stimulated macrophages and polymorphonuclear leucocytes in the presence of acetate and acetylCoA (120-122). Platelet aggregation is (potentially) elevated in diabetic patients (123, 124), and the degradation of PAF is significantly increased in serum from diabetics (125). This degradation is catalysed by plasma PAF-specific acetylhydrolase (21, 126, 127) an enzyme strongly associated with plasma lipoproteins (22, 128, 129), and correlation exists between the plasma lipid/lipoprotein concentrations and the capacity to degrade PAF (130), with lipoproteins possibly exerting a regulatory function on PAF degradation (131). The abnormal serum lipid concentrations of diabetics (125) may therefore explain the enhanced PAF degradation; the latter phenomenon is also seen in other pathological conditions associated with abnormal plasma lipids myocardial infarction and peripheral atherosclerosis (132). The relationship between PAF synthesis in endothelial cells (133, 134) and its degradation via plasma lipoprotein-associated acetylhydrolase, and subsequent vascular disease requires further clarification. A recent development is the observation that PAF appears to be able to stimulate cultured hepatoma cells (HEP-G2) to increase production of secreted PAF-acetylhydrolase (135).

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REMARKS

It is now clear that administration

of PAF has a number of metabolic effects and the key questions are whether these are of functional relevance or are merely obligatory events linked to the other cellular effects of PAF. In the case of hepatic glycogenolysis and increased glucose output in perfused liver it would appear that this is primarily mediated via the vasoconstrictive action of PAF resulting in decreased hepatic oxygenation. It is likely that the site of binding of PAF is the Kupffer cell surface and that this initiates a receptor-mediated influx of Ca2+, either directly or via stimulation of phosphoinositide metabolism. The result is contraction of the sinusoids, decreased perfusate flow and hence lower oxygen delivery which stimulates glycogenolysis in parenchymal cells. An alternative view is that PAF-binding to Kupffer cell receptors generates eicosanoids, particularly prostaglandin D2, which in turn can stimulate glycogenolysis directly in adjoining parenchymal cells. Whatever the precise mechanism the end result in stress situations is increased glucose availability for peripheral tissues, in particular the brain. As the transport of glucose into nervous tissue is not insulin-sensitive, the decrease in plasma insulin observed after PAF administration (102) would not be deleterious and would be expected to decrease glucose utilisation by muscle and adipose tissue in which glucose transport is insulin-sensitive. In the case of the changes in lipid metabolism in vivo induced by PAF, the functional significance is less certain (136). It is possible that the hypertriglyceridaemia and increased lipolysis in septic states represents a redirection and increased supply of lipid substrate to cells of the immune system (inflammatory reaction) and to muscle, thus sparing glucose for nervous tissue (136). The latter effect would be particularly important in stress states (shock, sepsis, burns) because of the relative lack of alternate substrates for the brain due to the accompanying hypoketonaemia (137). The inability as yet to demonstrate an effect of PAF on lipid metabolism in a system in vitro has hampered progress in elucidating its mechanism of action. The possibility that the apparent absence of an effect in vitro, particularly with liver preparations, may be due to the rapid degradation of PAF (138) cannot be excluded. Further work is required to determine the mechanisms for the hypertriglyceridaemia (decreased peripheral utilisation and/or increased hepatic synthesis and secretion of VLDL) and the increased hepatic synthesis of lipid on administration of PAF.

Acknowledgements We thank Mrs. M. Barber for preparation of the typescript. DHW is a member of the Medical Research Council (UK) External Scientific Staff.

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Editor’s review cross references: 1. Jeremy J Y, Mikhailidis D P, Dandona P. Excitatory receptor-prostanoid synthesis coupling in smooth muscle: mediation by calcium, protein kinase C and E proteins. Prostagl-Leukotr E&entl Fatty Acids-Reviews 1988: 34: 215-227. 2. Peplow P V, Mikhailibis D P. Platelet-activating factor (PAF) and its relation to prostaglandins, leukotrienes and other aspects of arachidonate metabolism. Prostagl Leukotr Essentl Fatty Acids 1990; 41: 71-82.