Fructose is a monosaccharide that is widely available in natural food sources such as fruits and honey. However, in most countries the main source of fructose is from sucrose, a disaccharide composed of equal portions of fructose and glucose. In the United States another major source of fructose is high-fructose corn syrup (HFCS), which is a commercial liquid product consisting of fructose and glucose in varying proportions, but which in soft drinks is usually 55% fructose and 45% glucose.
Fructose intake has increased markedly over the last 2 centuries, primarily due to the increasing intake of sucrose and HFCS [1
]. In particular, the introduction of HFCS in the 1970s resulted in an accelerated intake of added sugars in the USA, in part because HFCS was inexpensive and could be easily mixed in with processed foods [4
]. It has been suggested that the increase in added sugars worldwide may partially explain the marked increase in frequency of overweight and obese humans and may explain the rising frequency of metabolic syndrome, diabetes, hypertension, and cardiovascular diseases (coronary artery disease, congestive heart failure, stroke, and chronic kidney disease) [1
Fructose is absorbed into the intestine enterocyte by the Glut-5 specific transporter. While some fructose is metabolized in the small intestinal wall, much of it is passed via the portal vein to the liver, with perhaps 20 to 30% escaping into the systemic circulation [5
]. Within the hepatocyte, fructose is phosphorylated to fructose-1-phosphate by fructokinase. Because this reaction has no negative feedback system, if sufficient fructose is present, intracellular phosphate and ATP depletion can transiently occur. This results in the generation of AMP which is metabolized by AMP deaminase to inosine monophosphate and eventually to uric acid [5
]. The transient ATP depletion has some similarities to ischemia and can result in arrest of protein synthesis with the induction of oxidative stress and inflammation [7
Circulating fructose is taken up by a variety of cell types, including endothelial cells, but also is excreted into the urine where it is absorbed via the Glut-5 transporter into the S3 segment of the proximal tubule. This cell also expresses fructokinase; as such, the metabolism of fructose by this proximal tubular cell can also lead to local oxidative stress and inflammation [8