Purinergic Signaling in Liver Pathophysiology

Abstract

Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors. Furthermore, purinergic P2X ion channels are activated by ATP. These receptors are expressed in liver resident cells and play a critical role in maintaining liver function. In the normal physiology, these receptors regulate hepatic metabolic processes such as insulin responsiveness, glycogen and lipid metabolism, and bile secretion. In disease states, ATP and other nucleotides serve as danger signals and modulate purinergic responses in the cells. Recent studies have demonstrated that purinergic receptors play a significant role in the development of metabolic syndrome associated non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, hepatocellular carcinoma (HCC) and liver inflammation. In this concise review, we dissect the role of purinergic signaling in different liver resident cells involved in maintaining healthy liver function and in the development of the above-mentioned liver pathologies. Moreover, we discuss potential therapeutic strategies for liver diseases by targeting adenosine, P2Y and P2X receptors.

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis

“…Even circulating adenosine and nucleotides may stimulate hepatic glycogenolysis [ 41 ]. This may involve purinergic signaling via G-protein-coupled receptors (GPCRs) activated by adenosine or nucleotides [ 42 , 43 , 44 , 45 ]. Speculatively, endocannabinoids might also influence hepatic glucose metabolism via GPCRs [ 46 ].…”

Correlations between P2RX1 Expression and Gastrointestinal Cancers Prognosis and Immune Infiltration Based on Bioinformatics Analysis

“…Purinergic receptor family molecules mainly include 7 members, which are widely involved in many biological processes, such as energy metabolism, inflammatory response, and cell proliferation [14][15][16] . A large number of studies have confirmed that ATP-mediated purine signals play an important role in cancer progression and immune regulation [17][18][19][20] . As a member of P2X receptor family, P2RX1 is involved in mediating synaptic transmission between neurons or smooth muscle, arterial vasoconstriction, reproductive regulation, apoptosis, and so on.…”

Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation

“…Adenosine is a ubiquitous nucleotide metabolite that rapidly increases within the extracellular space in several stress and distress conditions, modulating tissue function and damage [11,12]. The liver is centrally involved in nucleotide production and metabolism, and increasing evidence shows that nucleotide metabolites have a main role in modulating liver health and disease [13,14]. Adenosine, in fact, both regulates physiological liver processes like carbohydrate and lipid metabolism and acts as a damaging or protective agent, promoting or preventing different hepatic pathologies such as fibrosis, steatohepatitis, carcinogenesis and ischemia-reperfusion injury [14].…”

“…Adenosine is signaled by activating the four G-coupled adenosine receptors (ARs): A1AR, A2AAR, A2BAR and A3A [11,12,15]. All ARs are expressed in the liver [13,14] and among them, A1AR and A2AAR display the highest affinity for adenosine [11,13].…”