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0706
EFFECTS OF EXTRACELLULAR ATP Iii HEPATOGYTES
ketone bedy formatien is deprassed while CO
2 productien
ia enhanced. Thus axtracellular ATP may reduce
tite antry of fatty acyl-CeA into hapatie mitecitendria
and divart mitochondriail acetyl-CoA inte tite tncarbexylic
acid cycla at tite expense of tite keteganic pathway.
Tite atimulation of CO2 fermation 2~-mobilizing itas alse aganta beensucit observad
as vasopresain in the case andofa etiter Ca
1-adrenergic agents (e.g., sea Re!s.
6, 11, 22), witareas tha inhibition of itepatic CPT-I
activity and ketogenasis by vasopreasin (11, 22) and
a1-adrenergic agenists (results net sitewn) itas been
deseribad as well. Heweyar, otitara haya reportad titat
a1-adrenargic agenta stimulata er haya no effect en
itepatic katoganesis (cf Re!. 13). In any case, eur rasults
are in agraamant witit the netion titat apart frem CPT-I
otitar factors may exert control ovar tite fatty acidexidativa
precass in the liver at tite intramiteehondrial
layal (sea Rafs. 13 and 30 for reviaw).
Tite effects of extracallular Al? and otiter Ca 2t~
ACC (and hence of fatty acid synthasis de nove) by
mebilizing effectera en livar metabolism are believed te
be dependant en receptor-mediated breakdewn of membrana
phespitatidylinoaitel 4,5-bispitespitate te produce
diacylglycerel and inositol 1,4,5-trispitoapitata
(1, 6). Extracallular ATP is also able te trigger tite
recepter-mediated hydrelysis of piteaphatidylciteline
and pitospitatidyletitalielamifle by membrana phospitoupases
(8, 9). In soma cali types, sucit as platalata and
varleus secretory calís, tite diacylglycarol and the ineaitel
1,4,5-trispitespitate limbs of phosphelipid hydrelysis
act aynargically (1). However, titis is not tite case witit
itepatocytes. Thus it has been sitewn titat tite stimulation
of glycegan breakdown, gluconeoganesis, and tite
tricarboxylic acid cycla inducad by Ca2~-mobi1izing
agenta in rat liver solely depends en the inesitel
1,4,5-trispitespitate cempenant of membrana phospitoinositida
itydrelysis, i.a., en tite elevatien of [Ca2>]
1(6, 8,
9). Howaver, tite effecta of extracellular ATP en itepatic
fatty acid metaboliam, as shewn in tite prasent papar,
saam te be mere cemplax (Fig. 4). Titus tite inhibition of
extracellular Al? may be inadiated by tite elavation of
[Ca2t (as
shown by tite lack of petantiatien of tite PMA effect by
BHQ, titapsigargin, andA-23187).
Because PMA inhibits CPT-I actiyity, it might be
argued that inhibition of PKC by bisindelylmaleimide
sitould cause an activation of CPT-I. Hewaver, it sitouid
be pointed eut that tite basal activity of itepatecellular
PKC ja very low bacause mest of tite anzyme is presant
in tite soluble fraction (a.g., sea Raf. 28). merafora,
inhibition of this marginal aetivity of PiCO should net
haya any important affect en CPT-I activity. In contrast,
bisindelylmaieimida sitonid be expected te abelish
PiCO-mediatad aventa witen PiCO is fully activatad
by itepatocyte incubation witit pitorbol estara. Thus we
haya observad titat bisindelylmaleimida is abla te bleck
tite PMA-inducad inhibition of CPT-I activity (rasults
net sitown), indicating titat tite inlhihitery affect of PMA
en CPT-I ismadiated by activation of PI-CC.
Extracellular ATP itas been aitown te trigger in vitre
a nuinber ofbielogical responses in different ceil limes of
Fjg. 4. Diagram showirg effecta of extracallular
ATP en hepatic fatty acid
metabolism. laesitel 1,4,5-triBpheBphate
[hab of phosphoinositide 2~ connactien) hydroly- may be
sis rasponBibla (jo., thafor Cainhibition
ofACO (and
hence of fatty acid synthesis da novo)
and admulatien of tricarbexy¡ic acid
cycle. Tha diacytgtycerol compoaeat of
phosphelipid breakdown may modutate
the inhihitjon of CPT-I (and hanca of
ketogenesis from long-chain fatty acida).
Effect ofextraceltuiaxATP is shown
aB +, activation; —, inhibitioa; oro, no
effact. KB. katúna boches; LCFA, longchau,
fatty acids; PL, phospholipids;
TG. triacylglycaro¡s.
Extrocellulor >
ATP