Purinergic signaling in liver disease: calcium signaling and induction of inflammation

Purinergic signaling regulates many metabolic functions and is implicated in liver physiology and pathophysiology. Liver functionality is modulated by ionotropic P2X and metabotropic P2Y receptors, specifically P2Y1, P2Y2, and P2Y6 subtypes, which physiologically exert their influence through calcium signaling, a key second messenger controlling glucose and fat metabolism in hepatocytes. Purinergic receptors, acting through calcium signaling, play an important role in a range of liver diseases. Ionotropic P2X receptors, such as the P2X7 subtype, and certain metabotropic P2Y receptors can induce aberrant intracellular calcium transients that impact normal hepatocyte function and initiate the activation of other liver cell types, including Kupffer and stellate cells. These P2Y- and P2X-dependent intracellular calcium increases are particularly relevant in hepatic disease states, where stellate and Kupffer cells respond with innate immune reactions to challenges, such as excess fat accumulation, chronic alcohol abuse, or infections, and can eventually lead to liver fibrosis. This review explores the consequences of excessive extracellular ATP accumulation, triggering calcium influx through P2X4 and P2X7 receptors, inflammasome activation, and programmed cell death. In addition, P2Y2 receptors contribute to hepatic steatosis and insulin resistance, while inhibiting the expression of P2Y6 receptors can alleviate alcoholic liver steatosis. Adenosine receptors may also contribute to fibrosis through extracellular matrix production by fibroblasts. Thus, pharmacological modulation of P1 and P2 receptors and downstream calcium signaling may open novel therapeutic avenues.