Figure 3.

Metabolism of fructose in the liver. Fructose enters hepatocytes and is phosphorylated to fructose 1-phosphate by ketohexokinase C (KHK-C). Fructose 1-phosphate is converted to glyceraldehyde-3 phosphate and is a substrate for the synthesis of triacylglycerols and very-low-density lipoproteins (VLDL). Fructose intake can upregulate the ATP citrate lyase (ACLY) enzyme, promoting citrate breakdown to acetyl-CoA. Acetyl-CoA is converted to malonyl-coenzyme A (malonyl-CoA) by acetyl-CoA carboxylase (ACC-1). Elevated levels of malonyl-CoA inhibit β-oxidation through limiting carnitine palmitoyl transferase 1A, which promotes the accumulation of diacylglycerols and ceramides, causing hepatic dyslipidemia. Moreover, increased KHK-C activity exhausts adenosine triphosphate (ATP), generating adenosine diphosphate (ADP), which is converted to adenosine monophosphate (AMP). In turn, AMP is transformed to inosine monophosphate (IMP), increasing purine production. Xanthine oxidoreductase (XO) produces oxygen reactive species (ROS), hydrogen peroxide (H2O2), 4-hydroxynonenal (4-HNE), and xanthine. Then, xanthine is metabolized, resulting in the overproduction of uric acid and ROS, which induce oxidative stress. Uric acid activates nuclear factor-κB (NF-κB), triggering inflammation.