Purinergic signalling in the liver in health and disease

Abstract

Purinergic signalling is involved in both the physiology and pathophysiology of the liver. Hepatocytes, Kupffer cells, vascular endothelial cells and smooth muscle cells, stellate cells and cholangiocytes all express purinoceptor subtypes activated by adenosine, adenosine 5′-triphosphate, adenosine diphosphate, uridine 5′-triphosphate or UDP. Purinoceptors mediate bile secretion, glycogen and lipid metabolism and indirectly release of insulin. Mechanical stress results in release of ATP from hepatocytes and Kupffer cells and ATP is also released as a cotransmitter with noradrenaline from sympathetic nerves supplying the liver. Ectonucleotidases play important roles in the signalling process. Changes in purinergic signalling occur in vascular injury, inflammation, insulin resistance, hepatic fibrosis, cirrhosis, diabetes, hepatitis, liver regeneration following injury or transplantation and cancer. Purinergic therapeutic strategies for the treatment of these pathologies are being explored.

Expression of mediators of purinergic signaling in human liver cell lines

“…Specifically, purinergic signals contribute to the maintenance of normal liver physiology via regulation of secretory [40,41] and metabolic [15] functions, as well as disease pathogenesis, via modulation of activation mechanisms in multiple hepatic cell types [21,42,43] and of wound healing and inflammatory responses [10,32,44]. Furthermore, the ecto-enzymes that control balance of extracellular nucleotides and nucleosides in the liver are equally important in pathological processes such …”

“…Of note, the purinergic signaling system is quite diverse, including multiple subtypes of G proteincoupled receptors for adenosine P1 receptors [24] and nucleotide P2Y receptors [25], nucleotide P2X ligand-gated ion channels [26], and a variety of plasma membrane-bound ecto-enzymes that regulate extracellular nucleotide/ nucleoside levels, namely ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases) [27,28], CD73/ecto-5′-nucleotidase [29,30], and tissue-non-specific alkaline phosphatase (TNAP) [31]. Thus, there is tremendous, almost overwhelming, complexity both in the relevant cell types and purinergic signaling systems relevant to liver physiology and disease [32].…”

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

“…Good glycolytic activity and glycemic control in the perioperative period will help to ensure adequate liver regeneration [92,93] .…”

Régénération hépatique

“…Cette molécule est détectée à la surface de la membrane plasmique par des récepteurs purinergiques métabotropiques (famille des récepteurs P2Y) ou ionotropiques (famille des récepteurs P2X) [8]. Dans le foie, chaque type cellulaire exprime son propre répertoire de récepteurs purinergiques qui sont impliqués dans plusieurs processus physiologiques et physiopathologiques pouvant influencer la régénération du foie [9,10]. L'équipe de T. Tordjmann avait déjà montré, chez l'homme et dans un modèle murin, qu'une résection hépa-tique provoquait une libération immé-diate d'ATP dans la circulation, en réponse à l'augmentation de la pression portale et intra-hépatique [11].…”

“…Ce phénotype pourrait s'expliquer par un défaut de protection du parenchyme hépatique, puisque les chercheurs ont observé une souffrance hépatique accrue chez les souris il-22 -/-ainsi qu'une augmentation du stress du réticulum dans leur foie. Kudira [2,9]. L'ATP libéré se fixe sur un récepteur purinergique, probablement le récepteur P2X1, présent à la surface des innate lymphoid cells, stimulant ainsi la libération d'IL-22 [2].…”