The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome.

NLRP3 inflammasome deficiency attenuates metabolic disturbances involving alterations in the gut microbial profile in mice exposed to high fat diet

“…Studies suggest a significant role of NLRP3 inflammasome in the initiation and progression of metaflammation (i.e., metabolically-induced inflammation) and related diseases, such as obesity, T2DM, NAFLD, and atherosclerosis [15][16][17] . NAFLD is the most common liver disease and there are several studies suggesting that NLRP3 inflammasome, bridging inflammation and fibrosis, could play an important role and potentially representing novel targets for therapy in this disorder [18][19][20] . In support of this hypothesis, we have demonstrated that NLRP3 inflammasome is functional in the heart with the potential to regulate cardiac function and cell death 21 .…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”

“…Damaged cells releasing ATP provoke activation of P2X7 and induce the NLRP3 inflammasome. As the authors highlight, these processes critically contribute to the induction of NAFLD and NASH [20].…”

“…Therefore, understanding of assembly, functionality and downstream signaling molecules of these multi-competent particles can open new opportunities in the treatment of inflammatory liver disease. In this context, regulatory aspects of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome are discussed by Rossato and colleagues [20]. In their review article, the authors discuss that the activation of this inflammasome is driven by extracellular ATP resulting in the activation of a specific purinergic, ligand-gated ion channel termed P2X7.…”

The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease?

“…In a broader perspective, emerging evidence shows the involvement of the P2X7R-NLRP3 inflammasome pathway in the induction of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, suggesting possible therapeutic strategies targeting the P2X7 receptor/NLRP3 inflammasome [ 99 ]. In a CCL4-induced, nonhuman primate model of liver fibrosis, treatment with a P2RX7 inhibitor (SGM-1019) improved histological characteristics of non-alcoholic steatohepatitis (NASH), protecting from liver inflammation and fibrosis [ 100 ].…”