The effect of liver-specific ketohexokinase deletion on the intestinal-liver-kidney axis in high-fructose-induced metabolic syndrome mice

The liver is a crucial site for fructose uptake and metabolism, a function intricately linked to fructose-associated pathologies. This study examines the role of hepatic ketohexokinase (KHK) in metabolic syndrome induced solely by high-fructose intake. Liver-specific <i>Khk</i>-deficient mice are generated and fed with a 20% fructose solution for 3 months, after which the features of metabolic syndrome are examined. Compared with fructose-fed floxed controls, fructose-fed liver-specific <i>Khk</i>-deficient mice present alleviated liver injury and hepatic steatosis, along with lower triglyceride levels in the plasma and liver, plasma aspartate transaminase and alanine transaminase levels, and mRNA levels of genes related to triglyceride and fatty acid synthesis. Liver-specific <i>Khk</i> deficiency also leads to lower uric acid levels in the plasma and urine, as well as xanthine oxidase activity and <i>Glut9</i> mRNA levels in the liver and kidneys of fructose-fed mice. Although intestinal villus length and epithelial barrier integrity remain unaffected, the deletion of liver <i>Khk</i> significantly reduces fructose-stimulated KHK, Glut2, Glut5, and aldolase B expression in the intestine and kidneys, suggesting inhibited fructose absorption and metabolism in these tissues. In the adipose tissue, fructose-induced increases in adipocyte size and tumor necrosis factor-α and interleukin-6 mRNA levels are blocked by liver-specific <i>Khk</i> deficiency, indicating improved remodeling of adipose tissue and reduced inflammation in adipocytes. Overall, liver-specific <i>Khk</i> deletion is sufficient to protect against metabolic syndrome induced by excessive fructose intake. Our findings underscore the critical role of liver KHK-mediated fructose metabolism in driving the physiological and pathological consequences associated with fructose consumption along the intestinal-liver-kidney axis.