Fructose is a simple sugar that occurs naturally in fruits, vegetables, and honey. The industrial use of high-fructose corn syrup and sucrose has made it a common component of the modern diet. While fructose and glucose are both six-carbon sugars, the body handles them through distinctly different metabolic pathways. Understanding how the body processes fructose is important because its unique metabolism can lead to a rapid flood of molecular intermediates, especially when consumed in large quantities.
Absorption and Transport into Circulation
The journey of fructose begins in the small intestine, where it is transported from the intestinal lumen into the bloodstream. Unlike glucose, fructose absorption is not dependent on the sodium-glucose cotransporter (SGLT1) or insulin. Instead, fructose relies on the specific transport protein GLUT5, located on the apical surface of the enterocytes.
GLUT5 moves fructose across the cell membrane via facilitated diffusion. The capacity of GLUT5 can be a limiting factor, and high concentrations of fructose can exceed the transporter’s ability, leading to malabsorption in some individuals. Once inside the enterocyte, fructose exits the cell and enters the portal circulation.
This exit is primarily facilitated by the GLUT2 transporter, located on the basolateral membrane. GLUT2 is a low-affinity, high-capacity transporter that moves both fructose and glucose into the portal vein, carrying the absorbed fructose directly to the liver.
The Fructolysis Pathway in the Liver
The liver is where most ingested fructose is processed through a unique metabolic sequence known as fructolysis. This pathway begins when fructose enters the hepatocyte and is rapidly phosphorylated by the enzyme fructokinase.
This phosphorylation converts fructose into fructose-1-phosphate, a reaction that uses one molecule of adenosine triphosphate (ATP). The action of fructokinase is characterized by its speed and lack of regulatory control; unlike glucose metabolism, fructokinase activity is not subject to negative feedback or allosteric regulation.
The newly formed fructose-1-phosphate is then cleaved by the enzyme Aldolase B. Aldolase B splits the molecule into two three-carbon molecules: dihydroxyacetone phosphate (DHAP) and glyceraldehyde. These molecules are integrated into the standard glycolysis pathway, but they enter at a later stage.
This point of entry distinguishes fructose from glucose metabolism. Glucose breakdown is tightly regulated by phosphofructokinase-1 (PFK-1), which acts as the main rate-limiting step in glycolysis. Because DHAP and glyceraldehyde enter the pathway after the PFK-1 regulatory step, the normal controls governing carbohydrate breakdown are bypassed.
This absence of regulatory control allows for a rapid, unregulated flux of triose phosphates into subsequent metabolic pathways. The consequence of this rapid, unchecked processing is the overproduction of downstream metabolites, which drives effects on lipid and purine metabolism.
Metabolic Products and Downstream Effects
The unregulated rush of triose phosphates creates intermediates primarily destined for fatty acid synthesis, known as de novo lipogenesis. These intermediates are converted to acetyl-CoA, which serves as the building block for new fatty acids.
These newly synthesized fatty acids are packaged with cholesterol and proteins to form very-low-density lipoproteins (VLDL), which are exported into the bloodstream. This accelerated lipogenesis and VLDL production contribute to increased blood triglyceride levels and the accumulation of fat within the liver. Fructose is thus a more lipogenic sugar than glucose.
Another consequence of the unregulated fructokinase step is the generation of uric acid. The initial phosphorylation of fructose consumes ATP faster than it can be replenished, leading to ATP depletion. This ATP is broken down into adenosine diphosphate (ADP) and then adenosine monophosphate (AMP).
The accumulated AMP is channeled into the purine degradation pathway, where it is ultimately converted into uric acid. This increased uric acid production is a direct result of the rapid, unregulated consumption of ATP in the first step of fructolysis.
While most fructose metabolites are directed toward lipid synthesis, some are also converted to lactate or glycogen. Up to a quarter of the ingested fructose can be converted to lactate, which is released into the circulation and utilized by other tissues for energy. Additionally, some DHAP is directed toward glycogen synthesis.