ATP release after partial hepatectomy regulates liver regeneration in the rat.
OBJECTIVE
Paracrine interactions are critical to liver physiology, particularly during regeneration, although physiological involvement of extracellular ATP, a crucial intercellular messenger, remains unclear. The physiological release of ATP into extracellular milieu and its impact on regeneration after partial hepatectomy were investigated in this study.


METHODS
Hepatic ATP release after hepatectomy was examined in the rat and in human living donors for liver transplantation. Quinacrine was used for in vivo staining of ATP-enriched compartments in rat liver sections and isolated hepatocytes. Rats were treated with an antagonist for purinergic receptors (Phosphate-6-azo(benzene-2,4-disulfonic acid), PPADS), and liver regeneration after hepatectomy was analyzed.


RESULTS
A robust and transient ATP release due to acute portal hyperpressure was observed immediately after hepatectomy in rats and humans. Clodronate liposomal pre-treatment partly inhibited ATP release in rats. Quinacrine-stained vesicles, co-labeled with a lysosomal marker in liver sections and isolated hepatocytes, were predominantly detected in periportal areas. These vesicles significantly disappeared after hepatectomy, in parallel with a decrease in liver ATP content. PPADS treatment inhibited hepatocyte cell cycle progression after hepatectomy, as revealed by a reduction in bromodeoxyuridine incorporation, phosphorylated histone 3 immunostaining, cyclin D1 and A expression and immediate early gene induction.


CONCLUSIONS
Extracellular ATP is released immediately after hepatectomy from hepatocytes and Kupffer cells under mechanical stress and promotes liver regeneration in the rat. We suggest that in hepatocytes, ATP is released from a lysosomal compartment. Finally, observations made in living donors suggest that purinergic signalling could be critical for human liver regeneration.
Gonzales
Emmanuel
E
Univ Paris-Sud, UMR-S 757, Orsay, F-91405, France.
Julien
Boris
B
Serrière-Lanneau
Valérie
V
Nicou
Alexandra
A
Doignon
Isabelle
I
Lagoudakis
Laura
L
Garcin
Isabelle
I
Azoulay
Daniel
D
Duclos-Vallée
Jean-Charles
JC
Castaing
Denis
D
Samuel
Didier
D
Hernandez-Garcia
Andres
A
Awad
Samir S
SS
Combettes
Laurent
L
Thevananther
Sundararajah
S
Tordjmann
Thierry
T
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006498:Hepatectomy / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000601:surgery*; D008115:Liver Regeneration / Q000502:physiology*; D016031:Liver Transplantation; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013314:Stress, Mechanical; D014019:Tissue Donors
D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate