JHEP reports : innovation in hepatology · 2026
The purinergic receptor P2X4R impacts lipid droplet size in fatty liver by stimulating macroautophagy.
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Pebrier Thibault, Garcin Isabelle, Fayol Olivier, Muthukulavan Marzaan, Doignon Isabelle, Bouzhir Latifa, Gautherot Julien, Cauchois Florent, Dellis Olivier, Le Guilcher Camille, Guettier Catherine, Merlen Grégory, Tordjmann Thierry
Аннотация
BACKGROUND & AIMS: P2X4R is a lysosomal ATP-gated cation channel receptor, playing roles in liver pathophysiology through poorly understood mechanisms. We aim at defining the role of P2X4R in macroautophagy and lipid droplet (LD) homeostasis.
METHODS: We used P2X4R-KO, LC3-GFP transgenic and WT mice, a specific P2X4R antagonist (BAY1797), and three experimental models of steatosis (n = 5-10 mice per group). Autophagic flux was measured in human embryonic kidney reporter cell line, and Atg5-/- mouse embryonic fibroblasts. Oleic acid cell loading, Oil Red O and LipidTox cell and tissue staining, and LC3-II Western blotting were performed.
RESULTS: The autophagic flux in the liver and in primary isolated hepatocytes was decreased in P2X4R-KO mice compared with WT mice, as well as in BAY1797 (compared with vehicle)-treated WT animals and hepatocytes. P2X4R overexpression stimulated the autophagic flux, indicating an impact of P2X4R on lysosome-autophagosome fusion. BAY1797 treatment in fasted mice as well as in both methionine- and choline-deficient diet and high-fat, high-sucrose, cholesterol-containing diet models resulted in small LD instead of large LD steatosis (vehicle-treated mice) and stimulated cytosolic lipolysis. Similarly, BAY1797 inhibited lipophagy and stimulated cytosolic lipolysis in vitro in oleic acid-loaded primary hepatocytes and in mouse embryonic fibroblasts, resulting in smaller LDs. Lysosome position analysis upon starvation revealed that P2X4R inhibition interfered with lysosomal trafficking in vitro. In patients with metabolic dysfunction-associated steatotic liver disease (n = 24), we found a correlation between LD size, autophagic flux, and P2X4R expression.
CONCLUSIONS: P2X4R inhibition decreased the autophagic flux in hepatocytes, resulting in LD size reduction, during fasting- as well as diet-induced steatosis in mice. P2X4R is proposed as a new therapeutic target to modulate lipophagy in the liver.
IMPACT AND IMPLICATIONS: We provide in vitro and in vivo evidence that P2X4R is a regulator of macroautophagy, and thereby affects LD homeostasis in the liver. Both genetic deletion and specific pharmacological inhibition of P2X4R results in LD size reduction in three murine models of fatty liver, in association with inhibition of lipophagy, stimulation of lipolysis, and reduction of liver inflammation. Finally, in a series of human patients with MASLD, we found that P2X4R expression correlated with autophagic flux and LD size. Thus, based on our data, we report that P2X4R inhibition is hepatoprotective in the context of MASLD.
METHODS: We used P2X4R-KO, LC3-GFP transgenic and WT mice, a specific P2X4R antagonist (BAY1797), and three experimental models of steatosis (n = 5-10 mice per group). Autophagic flux was measured in human embryonic kidney reporter cell line, and Atg5-/- mouse embryonic fibroblasts. Oleic acid cell loading, Oil Red O and LipidTox cell and tissue staining, and LC3-II Western blotting were performed.
RESULTS: The autophagic flux in the liver and in primary isolated hepatocytes was decreased in P2X4R-KO mice compared with WT mice, as well as in BAY1797 (compared with vehicle)-treated WT animals and hepatocytes. P2X4R overexpression stimulated the autophagic flux, indicating an impact of P2X4R on lysosome-autophagosome fusion. BAY1797 treatment in fasted mice as well as in both methionine- and choline-deficient diet and high-fat, high-sucrose, cholesterol-containing diet models resulted in small LD instead of large LD steatosis (vehicle-treated mice) and stimulated cytosolic lipolysis. Similarly, BAY1797 inhibited lipophagy and stimulated cytosolic lipolysis in vitro in oleic acid-loaded primary hepatocytes and in mouse embryonic fibroblasts, resulting in smaller LDs. Lysosome position analysis upon starvation revealed that P2X4R inhibition interfered with lysosomal trafficking in vitro. In patients with metabolic dysfunction-associated steatotic liver disease (n = 24), we found a correlation between LD size, autophagic flux, and P2X4R expression.
CONCLUSIONS: P2X4R inhibition decreased the autophagic flux in hepatocytes, resulting in LD size reduction, during fasting- as well as diet-induced steatosis in mice. P2X4R is proposed as a new therapeutic target to modulate lipophagy in the liver.
IMPACT AND IMPLICATIONS: We provide in vitro and in vivo evidence that P2X4R is a regulator of macroautophagy, and thereby affects LD homeostasis in the liver. Both genetic deletion and specific pharmacological inhibition of P2X4R results in LD size reduction in three murine models of fatty liver, in association with inhibition of lipophagy, stimulation of lipolysis, and reduction of liver inflammation. Finally, in a series of human patients with MASLD, we found that P2X4R expression correlated with autophagic flux and LD size. Thus, based on our data, we report that P2X4R inhibition is hepatoprotective in the context of MASLD.