Abstract

Aim Excessive fructose consumption is strongly linked to metabolic syndrome. Dietary fructose is predominantly transported into cells through the solute carrier family 2 member 5 and/or member 2, and then metabolized by fructokinase (also known as ketohexokinase, KHK), which is primarily expressed in the intestine, liver, and kidney. The significant contribution of KHK-mediated fructose metabolism in the intestine or liver to sugar-induced metabolic syndrome has been well documented. This study aimed to elucidate the pathophysiological significance of renal KHK-mediated fructose metabolism in the pathogenesis of fructose-induced metabolic syndrome. Methods A mouse model with inducible deletion of both KHK isoforms (KHK-A and KHK-C) in renal tubules was generated using the Cre-LoxP recombination system. We then systematically evaluated parameters associated with fructose-induced metabolic syndrome in these mice fed a 20% fructose solution (w/v). Results In mice receiving excess fructose solutions, the inducible deletion of KHK via the Pax8-rtTA/LC1 system entirely blocks fructose metabolism and is sufficient to prevent the development of metabolic syndrome. The latter is evidenced by improved glucose and insulin resistance, alleviated hepatic steatosis and liver injury, mitigated adipose tissue remodeling, and strengthened colonic epithelial barrier integrity in fructose-fed Khk -deficient mice. These protections are likely attributed to the reduced uric acid generation resulting from the blockade of fructose metabolism. Conclusion Our findings suggest that KHK-mediated fructose metabolism in the kidneys may be crucial for the development of fructose-induced metabolic syndrome.