Aryl Hydrocarbon Receptor regulates uric acid homeostasis.

Abstract

Gout is the most common form of arthritis, and results from reduced renal excretion of uric acid. A link between environmental pollution and hyperuricemia has been identified, but the underlying mechanisms remain unknown. Our aim was to determine whether the Aryl Hydrocarbon Receptor (AHR), one of the main mediators of the toxicity of environmental pollutants, could be involved in uric acid homeostasis. Murine models based on pharmacological activation of AHR were used, as well as a mouse model with Ahr gene knockout, to analyze the impact of this receptor on renal uric acid excretion. Based on the initial results, additional mouse models were used to identify the links between AHR, gluconeogenesis and renal uric acid excretion. A study was also conducted in four patients affected by glycogen storage disease. Activation of AHR by dioxin-like agonists decreases renal uric acid excretion, while its genetic deletion in mouse models increase renal uric acid excretion. AHR does not modulate renal uric acid transporters, but alters gluconeogenic processes and lactate metabolism in hepatocytes. Lactate is exchanged for uric acid in the renal proximal tubule, reducing renal uric acid excretion. The study in patients confirms that gluconeogenesis is a major determinant of uric acid homeostasis. These results highlight the major role of AHR and gluconeogenesis in the regulation of uric acid homeostasis.